The present invention is directed to xcex3-hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamide compounds, their pharmaceutically acceptable salts, their synthesis, and their use as inhibitors of HIV protease. The compounds of the present invention are useful for preventing or treating infection by HIV and for treating AIDS.
References are made throughout this application to various publications in order to more fully describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference in their entireties for all purposes.
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl et al., Proc. Nat""l Acad. Sci. 1988, 85: 4686, demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicated that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner et al., Nature 1985, 313: 277]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh et al., EMBO J. 1985, 4: 1267; Power et al., Science 1986, 231: 1567; Pearl et al., Nature 1987, 329: 351].
Several HIV protease inhibitors are presently in clinical use for the treatment of AIDS and HIV infection, including indinavir (see U.S. Pat. No. 5,413,999), nelfinavir (U.S. Pat. No 5,484,926), saquinavir (U.S. Pat. No. 5,196,438), and ritonavir (U.S. Pat. No. 5,484,801). Each of these protease inhibitors is a peptidomimetic, competitive inhibitor of the viral protease which prevents cleavage of the HIV gag-pol polyprotein precursor. Indinavir, for example, has been found to be highly effective in reducing HIV viral loads and increasing CD4 cell counts in HIV-infected patients, when used in combination with nucleoside reverse transcriptase inhibitors. See, for example, Hammer et al., New England J. Med. 1997, 337: 725-733 and Gulick et al., New England J. Med. 1997, 337: 734-739.
A substantial and persistent problem in the treatment of AIDS has been the ability of the HIV virus to develop resistance to the therapeutic agents employed to treat the disease. Resistance to HIV-1 protease inhibitors has been associated with 25 or more amino acid substitutions in both the protease and the cleavage sites. Many of these viral variants are resistant to all of the HIV protease inhibitors currently in clinical use. See Condra et al., Drug Resistance Updates 1998, 1: 1-7; Condra et al., Nature 1995, 374: 569-571; Condra et al., J. Virol. 1996, 70: 8270-8276; Patrick et al., Antiviral Ther. 1996, Suppl. 1: 17-18; and Tisdale et al., Antimicrob. Agents Chemother. 1995, 39: 1704-1710.
Attempts to address the resistance issue with xe2x80x9csalvage therapyxe2x80x9d consisting of high doses of multiple protease inhibitors have only been moderately successful due to the high level of cross resistance and toxicities associated with these protease inhibitors. Accordingly, there remains a need for new protease inhibitors having improved effectiveness against the viral variants.
The present invention is directed to novel protease inhibitors which are much more potent against HIV viral mutants than the known protease inhibitors.
The present invention provides a novel group of xcex3-hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamide compounds which are potent inhibitors of HIV protease including mutant forms thereof that are resistant to known protease inhibitors. These compounds are useful in the inhibition of HIV protease, the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS and/or ARC, when employed as compounds or pharmaceutically acceptable salts or hydrates (when appropriate) thereof, optionally as pharmaceutical composition ingredients, and optionally in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. More particularly, the present invention includes a compound of Formula (I): 
wherein
R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; wherein
(i) each of the substituents on substituted aryl is independently
(a) halogen,
(b) cyano,
(c) hydroxy,
(d) C1-C6 alkyl,
(e) C2-C6 alkenyl,
(f) C2-C6 alkynyl,
(g) fluorinated C1-C6 alkyl,
(h) C1-C6 alkoxy,
(i) fluorinated C1-C6 alkoxy,
(j) Sxe2x80x94(C1-C6 alkyl),
(k) heterocycle, or
(l) heterocycle substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, Sxe2x80x94(C1-C6 alkyl), and NRaRb;
(ii) each of the substituents on substituted heteroaryl is independently
(a) halogen,
(b) cyano,
(c) hydroxy,
(d) NRaRb,
(e) C1-C6 alkyl,
(f) C2-C6 alkenyl,
(g) C2-C6 alkynyl,
(h) fluorinated C1-C6 alkyl,
(i) C1-C6 alkoxy,
(j) fluorinated C1-C6 alkoxy,
(k) Sxe2x80x94(C1-C6 alkyl),
(l) phenyl,
(m) phenyl substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, and Sxe2x80x94(C1-C6 alkyl),
(l) heterocycle, or
(m) heterocycle substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, Sxe2x80x94(C1-C6 alkyl), NRaRb, and a 5AAAAAAA- or 6-membered heteroaromatic ring consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, O and S;
R2 and R3 are each independently hydrogen or C1-C4 alkyl; or R2 and R3 together with the carbon to which they are attached form C3-C6 cycloalkyl;
R4 is C1-C6 alkyl, C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; wherein each of the substituents on substituted aryl is independently halogen, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, or heteroaryl; and each of the substituents on substituted heteroaryl is independently halogen, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, or aryl;
R5 is carbocyclic, substituted carbocyclic, heterocyclic or substituted heterocyclic, wherein each of the substituents on substituted carbocyclic or substituted heterocyclic is independently halogen, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, fluorinated C1-C6 alkyl, or C1-C6 alkoxy;
R6 is fluorinated C1-C6 alkyl; and
Ra and Rb are each independently hydrogen or C1-C4 alkyl; or Ra and Rb together with the nitrogen to which they are attached form C3-C6 azacycloalkyl;
or a pharmaceutically acceptable salt thereof.
The present invention also includes pharmaceutical compositions containing a compound of the present invention and methods of preparing such pharmaceutical compositions. The present invention further includes methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV. The present invention also includes methods for making compounds of the present invention and methods for making intermediates useful in the preparation of compounds of the present invention.
These and other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples, and appended claims.
The present invention includes the compounds of Formula (I) above. These compounds and their pharmaceutically acceptable salts are HIV protease inhibitors.
A first embodiment of the present invention is a compound of Formula (I), wherein
R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; wherein
(i) each of the substituents on substituted aryl is independently
(a) halogen,
(b) cyano,
(c) hydroxy,
(d) C1-C6 alkyl,
(e) C2-C6 alkenyl,
(f) C2-C6 alkynyl,
(g) fluorinated C1-C6 alkyl,
(h) C1-C6 alkoxy,
(i) heterocycle, or
(j) heterocycle substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, and NRaRb;
(ii) each of the substituents on substituted heteroaryl is independently
(a) halogen,
(b) cyano,
(c) hydroxy,
(d) NRaRb,
(e) C1-C6 alkyl,
(f) C2-C6 alkenyl,
(g) C2-C6 alkynyl,
(h) fluorinated C1-C6 alkyl,
(i) C1-C6 alkoxy,
(j) phenyl,
(k) phenyl substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, fluorinated C1-C6 alkyl, and C1-C6 alkoxy,
(l) heterocycle, or
(m) heterocycle substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, and NRaRb;
and all other variables are as originally defined above;
or a pharmaceutically acceptable salt thereof.
A second embodiment of the present invention is a compound of Formula (I), wherein
R4 is C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl, wherein heteroaryl is selected from pyridyl, pyrazinyl, pyrimidinyl, thiophenyl, thiazolyl, pyridofuranyl, pyrimidofuranyl, pyridothienyl, pyridazothienyl, pyridooxazolyl, pyridazooxazolyl, pyrimidooxazolyl, pyridothiazolyl, and pyridazothiazolyl; and wherein each of the substituents on substituted phenyl or substituted heteroaryl is independently halogen, hydroxy, C1-C6 alkyl, fluorinated C1-C6 alkyl, or C1-C6 alkoxy;
and all other variables are as originally defined above;
or a pharmaceutically acceptable salt thereof.
A third embodiment of the present invention is a compound of formula(I), wherein
R4 is C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl, wherein heteroaryl is selected from pyridyl, pyrazinyl, pyrimidinyl, and thiophenyl; and wherein each of the substituents on substituted phenyl or substituted heteroaryl is independently halogen, hydroxy, C1-C6 alkyl, fluorinated C1-C6 alkyl, or C1-C6 alkoxy;
and all other variables are as defined in the first embodiment;
or a pharmaceutically acceptable salt thereof.
A first class of the present invention is a compound of Formula (I), wherein
R4is 
xe2x80x83each
Z is independently hydrogen, halogen, cyano, C1-C6 alkyl, or C1-C6 alkoxy; and
q is an integer from 0 to 2;
and all other variables are as defined in the second embodiment;
or a pharmaceutically acceptable salt thereof.
A second class of the present invention is a compound of Formula (I), wherein
R4 is 
xe2x80x83each
Z is independently hydrogen, halogen, cyano, C1-C6 alkyl, or C1-C6 alkoxy;
q is an integer from 0 to 2;
and all other variables are as defined in the third embodiment;
or a pharmaceutically acceptable salt thereof.
A fourth embodiment of the present invention is a compound of Formula (I), wherein
R5 is carbocyclic, substituted carbocyclic, heterocyclic or substituted heterocyclic, wherein carbocyclic is cyclopentyl, indanyl, or tetralin, and heterocyclic is chroman, thiochroman, or dioxoisothiochroman; wherein each of the substituents on substituted carbocyclic or substituted heterocyclic is independently halogen, hydroxy, C1-C6 alkyl, fluorinated C1-C6 alkyl, or C1-C6 alkoxy;
and all other variables are as originally defined or as defined in any one of the preceding embodiments or classes;
or a pharmaceutically acceptable salt thereof.
A third class of the present invention is a compound of Formula (I), wherein
R5 is 
xe2x80x83wherein
A is CRcRd, O, or S;
each Y is independently hydrogen, halogen, C1-C6 alkyl, fluorinated C1-C6 alkyl, or C1-C6 alkoxy;
Rc and Rd are each independently hydrogen or C1-C4 alkyl, or Rc and Rd together with the carbon to which they are attached from C3-C6 cycloalkyl;
Re is hydrogen, C1-C4 alkyl, fluorinated C1-C4 alkyl, or phenyl;
p is an integer from 0 to 2;
and all other variables are as defined in the fourth embodiment;
or a pharmaceutically acceptable salt thereof.
In a preferred aspect of the third class of the present invention, R5 is 
A fifth embodiment of the present invention is a compound of Formula (I), wherein,
R6 is 
xe2x80x83and all other variables are as originally defined or as defined in any of the preceding embodiments or classes;
or a pharmaceutically acceptable salt thereof.
In a preferred aspect of the fifth embodiment, R6 is 
A sixth embodiment of the present invention is a compound of Formula (I), wherein
R1 is C1-C6 alkyl, C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, wherein heteroaryl is (i) a 5- or 6-membered aromatic ring consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, S, and O or (ii) an 8- to 10-membered bicyclic ring system consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, S, and O, wherein at least one of the rings in the bicyclic system is an aromatic ring; wherein
(i) each of the substituents on substituted aryl is independently
(a) halogen,
(b) cyano,
(c) hydroxy,
(d) C1-C6 alkyl,
(e) C2-C6 alkenyl,
(f) C2-C6 alkynyl,
(g) fluorinated C1-C6 alkyl,
(h) C1-C6 alkoxy,
(i) fluorinated C1-C6 alkoxy,
(j) Sxe2x80x94(C1-C6 alkyl),
(k) heterocycle, or
(l) heterocycle substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, Sxe2x80x94(C1-C6 alkyl), and NRaRb;
(ii) each of the substituents on substituted heteroaryl is independently
(a) halogen,
(b) cyano,
(c) hydroxy,
(d) NRaRb,
(e) C1-C6 alkyl,
(f) C2-C6 alkenyl,
(g) C2-C6 alkynyl,
(h) fluorinated C1-C6 alkyl,
(i) C1-C6 alkoxy,
(j) fluorinated C1-C6 alkoxy,
(k) Sxe2x80x94(C1-C6 alkyl),
(l) phenyl,
(m) phenyl substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, and Sxe2x80x94(C1-C6 alkyl),
(l) heterocycle, or
(m) heterocycle substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, Sxe2x80x94(C1-C6 alkyl), NRaRb, and a 5- or 6-membered heteroaromatic ring consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, O and S;
and all other variables are as originally defined or as defined in any of the preceding embodiments or classes;
or a pharmaceutically acceptable salt thereof.
A seventh embodiment of the present invention is a compound of Formula (I), wherein
R1 is C1-C6 alkyl, C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, wherein heteroaryl is (i) a 5- or 6-membered aromatic ring consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, S, and O or (ii) an 8- to 10-membered bicyclic ring system consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, S, and O, wherein at least one of the rings in the bicyclic system is an aromatic ring; wherein
(i) each of the substituents on substituted aryl is independently
(a) halogen,
(b) cyano,
(c) hydroxy,
(d) C1-C6 alkyl,
(e) C2-C6 alkenyl,
(f) C2-C6 alkynyl,
(g) fluorinated C1-C6 alkyl,
(h) C1-C6 alkoxy,
(i) heterocycle, or
(j) heterocycle substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, and NRaRb;
(ii) each of the substituents on substituted heteroaryl is independently
(a) halogen,
(b) cyano,
(c) hydroxy,
(d) NRaRb,
(e) C1-C6 alkyl,
(f) C2-C6 alkenyl,
(g) C2-C6 alkynyl,
(h) fluorinated C1-C6 alkyl,
(i) C1-C6 alkoxy,
(j) phenyl,
(k) phenyl substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, fluorinated C1-C6 alkyl, and C1-C6 alkoxy
(l) heterocycle, or
(m) heterocycle substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, and NRaRb;
and all other variables are as originally defined or as defined in any of the preceding embodiments or classes;
or a pharmaceutically acceptable salt thereof.
A fourth class of the present invention is a compound of Formula (I), wherein
R1 is C1-C6 alkyl, C1-C6 cycloalkyl, phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl, wherein heteroaryl is pyridyl, methylenedioxyphenyl, furanyl, benzofuranyl, benzothiofuranyl, benzoxazolyl, benzothiazolyl, azabenzothiazolyl, azabenzoxazolyl, azabenzofuranyl, azabenzothiofuranyl, oxazolyl, thiazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, indazolyl, pyrrolyl, pyrazolyl, thiophenyl, or thienothiophenyl; and wherein
(i) each of the substituents on substituted phenyl is independently
(a) halogen,
(b) cyano,
(c) hydroxy,
(d) C1-C4 alkyl,
(e) fluorinated C1-C4 alkyl,
(f) C1-C4 alkoxy,
(g) fluorinated C1-C4 alkoxy,
(h) Sxe2x80x94(C1-C4 alkyl),
(i) heterocycle which is a 5- or 6-membered unsaturated monocyclic ring consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, O and S, or
(j) substituted heterocycle which is a 5- or 6-membered unsaturated monocyclic ring as defined in (i) substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl, C1-C4 alkoxy, fluorinated C1-C4 alkoxy, Sxe2x80x94(C1-C4 alkyl) and NRaRb; and
(ii) each of the substituents on substituted heteroaryl is independently
(a) halogen,
(b) cyano,
(c) hydroxy,
(d) NRaRb, if and only if the heteroaryl is pyridyl,
(e) C1-C4 alkyl,
(f) fluorinated C1-C4 alkyl,
(g) C1-C4 alkoxy,
(h) fluorinated C1-C4 alkoxy,
(i) Sxe2x80x94(C1-C4 alkyl),
(j) phenyl,
(k) phenyl substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl, C1-C4 alkoxy, fluorinated C1-C4 alkoxy, and Sxe2x80x94(C1-C4 alkyl),
(l) heterocycle which is a 5- or 6-membered unsaturated monocyclic ring consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, O and S;
(m) substituted heterocycle which is a 5- or 6-membered unsaturated monocyclic ring as defined in (l) substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl, C1-C4 alkoxy, fluorinated C1-C4 alkoxy, Sxe2x80x94(C1-C4 alkyl), NRaRb, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyrrolyl, furanyl, thienyl, isoxazolyl, and isothiazolyl;
and all other variables are as defined in the sixth embodiment;
or a pharmaceutically acceptable salt thereof.
A fifth class of the present invention is a compound of Formula (I), wherein
R1 is C1-C6 alkyl, C1-C6 cycloalkyl, phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl, wherein heteroaryl is pyridyl, methylenedioxyphenyl, furanyl, benzofuranyl, benzothiofuranyl, benzoxazolyl, benzothiazolyl, azabenzothiazolyl, azabenzoxazolyl, azabenzofuranyl, azabenzothiofuranyl, oxazolyl, thiazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, indazolyl, pyrrolyl, pyrazolyl, thiophenyl, or thienothiophenyl; and wherein
(i) each of the substituents on substituted phenyl is independently
(a) halogen,
(b) cyano,
(c) hydroxy,
(d) C1-C4 alkyl,
(e) fluorinated C1-C4 alkyl,
(f) C1-C4 alkoxy,
(g) heterocycle which is a 5- or 6-membered unsaturated monocyclic ring consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, O and S, or
(h) substituted heterocycle which is a 5- or 6-membered unsaturated monocyclic ring as defined in (g) substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl, C1-C4 alkoxy and NRaRb; and
(ii) each of the substituents on substituted heteroaryl is independently
(a) halogen,
(b) cyano,
(c) hydroxy,
(d) NRaRb, if and only if the heteroaryl is pyridyl,
(e) C1-C4 alkyl,
(f) fluorinated C1-C4 alkyl,
(g) C1-C4 alkoxy,
(h) phenyl,
(i) phenyl substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl , and C1-C4 alkoxy,
(j) heterocycle which is a 5- or 6-membered unsaturated monocyclic ring consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, O and S;
(k) substituted heterocycle which is a 5- or 6-membered unsaturated monocyclic ring as defined in (j) substituted with one or more substituents independently selected from halogen, cyano, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl, C1-C4 alkoxy and NRaRb.
and all other variables are as defined in the seventh embodiment;
or a pharmaceutically acceptable salt thereof.
In a preferred aspect of the fourth class, heterocycle in (i)(i) and in (ii)(l) are each independently 
and wherein
substituted heterocycle in (i)(j) is heterocycle as defined above with one or more substituents independently selected from halogen, cyano, C1-C4 alkyl, fluorinated C1-C4 alkyl, C1-C4 alkoxy, fluorinated C1-C4 alkoxy, and Sxe2x80x94(C1-C4 alkyl); and
substituted heterocycle in (ii)(m) is heterocycle as defined above with one or more substituents independently selected from halogen, hydroxy, cyano, C1-C4 alkyl, fluorinated C1-C4 alkyl, C1-C4 alkoxy, fluorinated C1-C4 alkoxy, Sxe2x80x94(C1-C4 alkyl), NRaRb, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyrrolyl, isoxazolyl, and isothiazolyl; or is 
In a preferred aspect of the fifth class, heterocycle in (i)(g) and in (ii)(j) are each independently 
and wherein
substituted heterocycle in (i)(h) is heterocycle as defined above with one or more substituents independently selected from halogen, cyano, C1-C4 alkyl, fluorinated C1-C4 alkyl, and C1-C4 alkoxy; and
substituted heterocycle in (ii)(k) is heterocycle as defined above with one or more substituents independently selected from halogen, cyano, C1-C4 alkyl, fluorinated C1-C4 alkyl, and C1-C4 alkoxy; or is 
An eighth embodiment of the present invention is a compound of Formula (I), wherein
R1 is 
each D is independently hydrogen, halogen, cyano, hydroxy, NRaRb, C1-C4 alkyl, C1-C4 alkoxy, fluorinated C1-C4 alkoxy, Sxe2x80x94(C1-C4 alkyl), phenyl, substituted phenyl, heterocycle, or substituted heterocycle; wherein substituted phenyl is phenyl with one or more subsituents independently selected from halogen, hydroxy, C1-C4 alkyl, and C1-C4 alkoxy; and wherein substituted heterocycle is heterocycle with one or more substituents independently selected from halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, fluorinated C1-C4 alkoxy, and Sxe2x80x94(C1-C4 alkyl);
each E is independently hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, heterocycle, or substituted heterocycle;
G and Gxe2x80x2 are each independently selected from hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl, and C1-C4 alkoxy;
J is 
xe2x80x83heterocycle, or substituted heterocycle;
each L is independently hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl, or C1-C4 alkoxy;
X is O or S;
heterocycle in each of D, E and J is independently 
xe2x80x83substituted heterocycle in each of E and J is independently heterocycle as defined above with one or more substituents independently selected from halogen, hydroxy, cyano, C1-C4 alkyl, fluorinated C1-C4 alkyl, C1-C4 alkoxy, fluorinated C1-C4 alkoxy, Sxe2x80x94(C1-C4 alkyl), NRaRb, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyrrolyl, isoxazolyl, and isothiazolyl; or is 
s, sxe2x80x2, and t are each independently integers from 0 to 2;
and all other variables are as originally defined or as defined in any of the preceding embodiments or classes;
or a pharmaceutically acceptable salt thereof.
A ninth embodiment of the present invention is a compound of Formula (I), wherein
R1 is 
each D is independently hydrogen, halogen, cyano, hydroxy, NRaRb, C1-C4 alkyl, C1-C4 alkoxy, phenyl, substituted phenyl, heterocycle, or substituted heterocycle; wherein substituted phenyl is phenyl with one or more subsituents independently selected from halogen, hydroxy, C1-C4 alkyl, and C1-C4 alkoxy; and wherein substituted heterocycle is heterocycle with one or more substituents independently selected from halogen, hydroxy, C1-C4 alkyl, and C1-C4 alkoxy;
each E is independently hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, heterocycle, or substituted heterocycle;
G and Gxe2x80x2 are each independently selected from hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl, and C1-C4 alkoxy;
J is 
xe2x80x83heterocycle, or substituted heterocycle;
each L is independently hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl, or C1-C4 alkoxy;
X is O or S;
heterocycle in each of D, E and J is independently 
substituted heterocycle in each of E and J is independently heterocycle as defined above with one or more substituents independently selected from halogen, cyano, fluorinated C1-C4 alkyl and C1-C4 alkoxy; or is 
s, sxe2x80x2, and t are each independently integers from 0 to 2;
and all other variables are as originally defined or as defined in any of the preceding embodiments or classes;
or a pharmaceutically acceptable salt thereof.
A sixth class of the present invention is a compound of Formula (I), wherein
R6 is 
xe2x80x83and all other variables are as defined in the eighth or the ninth embodiments.
A seventh class of the present invention is a compound of Formula (I), wherein
R4 is 
each Z is independently hydrogen, halogen, cyano, C1-C6 alkyl, or C1-C6 alkoxy;
q is an integer from 0 to 2;
and all other variables are as defined in the sixth class;
or a pharmaceutically acceptable salt thereof.
An eighth class of the present invention is a compound of Formula (I), wherein
R4 is 
each Z is independently hydrogen, halogen, cyano, C1-C6 alkyl, or C1-C6 alkoxy;
q is an integer from 0 to 2;
and all other variables are as defined in the sixth class;
or a pharmaceutically acceptable salt thereof.
A ninth class of the present invention is a compound of Formula (I), wherein
R1 is 
R2 and R3 are each independently hydrogen or C1-C4 alkyl; or R2 and R3 together with the carbon to which they are attached form C3-C6 cycloalkyl;
R4 is 
R5 is 
R6 is 
J is 
xe2x80x83heterocycle, or substituted heterocycle;
heterocycle is 
xe2x80x83substituted heterocycle is heterocycle as defined above having one or more substituents independently selected from halogen, C1-C4 alkoxy, C1-C4 alkyl, fluorinated C1-C4 alkoxy, fluorinated C1-C4 alkyl, xe2x80x94Sxe2x80x94CH3, xe2x80x94N(CH3)2, thiazolyl, and oxazolyl;
each L is independently hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl, or C1-C4 alkoxy;
X is O or S;
each Y is independently hydrogen, halogen, C1-C6 alkyl, fluorinated C1-C6 alkyl, or C1-C4 alkoxy;
p is an integer from 0 to 2; and
t is an integer from 0 to 2;
or a pharmaceutically acceptable salt thereof.
In a preferred aspect of the ninth class, R2 and R3 are each independently hydrogen or methyl;
each L is independently hydrogen, chlorine, or fluorine;
each Y is independently hydrogen, chlorine, or fluorine; and
each of the substituents on substituted heterocycle is independently chlorine, fluorine, methoxy, ethoxy, xe2x80x94OCF3, xe2x80x94OCHF2, methyl, ethyl, n-propyl, xe2x80x94Sxe2x80x94CH3, xe2x80x94N(CH3)2, and thiazolyl.
A tenth class of the present invention is a compound of Formula (I), wherein
R1 is 
R2 and R3 are each independently hydrogen or C1-C4 alkyl; or R2 and R3 together with the carbon to which they are attached form C3-C6 cycloalkyl;
R4 is 
R5 is 
R6 is 
J is 
xe2x80x83heterocycle, or substituted heterocycle;
heterocycle is 
xe2x80x83substituted heterocycle is heterocycle as defined above having one or more substituents independently selected from halogen and C1-C4 alkoxy;
each L is independently hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl, or C1-C4 alkoxy;
X is O or S;
each Y is independently hydrogen, halogen, C1-C6 alkyl, fluorinated C1-C6 alkyl, or C1-C4 alkoxy;
p is an integer from 0 to 2; and
t is an integer from 0 to 2;
or a pharmaceutically acceptable salt thereof.
In a preferred aspect of the tenth class, R2 and R3 are each independently hydrogen or methyl;
each L is independently hydrogen, chlorine, or fluorine;
each Y is independently hydrogen, chlorine, or fluorine; and
each of the substituents on substituted heterocycle is independently chlorine, fluorine, or methoxy.
An eleventh class of the present invention is a compound of Formula (I), wherein
R1 is 
R2 and R3 are each independently hydrogen or C1-C4 alkyl; or R2 and R3 together with the carbon to which they are attached form C3-C6 cycloalkyl;
R4 is 
R5 is 
R6 is 
J is 
xe2x80x83heterocycle, or substituted heterocycle;
heterocycle is 
xe2x80x83substituted heterocycle is heterocycle as defined above having one or more substituents independently selected from halogen, C1-C4 alkoxy, C1-C4 alkyl, fluorinated C1-C4 alkoxy, fluorinated C1-C4 alkyl, xe2x80x94Sxe2x80x94CH3, xe2x80x94N(CH3)2, thiazolyl and oxazolyl;
each L is independently hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl, or C1-C4 alkoxy;
X is O or S;
each Y is independently hydrogen, halogen, C1-C6 alkyl fluorinated C1-C6 alkyl, or C1-C4 alkoxy; and
p is an integer from 0 to 2;
t is an integer from 0 to 2;
or a pharmaceutically acceptable salt thereof.
In a preferred aspect of the eleventh class, R2 and R3 are each independently hydrogen or methyl;
each L is independently hydrogen, chlorine, or fluorine;
each Y is independently hydrogen, chlorine, or fluorine; and
each of the substituents on substituted heterocycle is independently chlorine, fluorine, methoxy, ethoxy, xe2x80x94OCF3, xe2x80x94OCHF2, methyl, ethyl, n-propyl, xe2x80x94Sxe2x80x94CH3, xe2x80x94N(CH3)2, and thiazolyl.
Exemplifying the invention are compounds selected from the group consisting of
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-4-(1-furo[3,2-c]pyridin-2-yl-1-methylethyl)-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-2-[[(2-fluoroethyl)amino]carbonyl]-4-(1-furo[3,2-c]pyridin-2-yl-1-methylethyl)-xcex3-hydroxy-xcex1-(phenylmethyl)-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzofuran-4-yl)-2-[[[2-fluoro-1,1-bis(fluoromethyl)ethyl]amino]carbonyl]-4-(1-furo[3,2-c]pyridin-2-yl-1-methylethyl)-xcex3-hydroxy-xcex1-(phenylmethyl)-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-2-[[[1,1-bis(fluoromethyl)ethyl]amino]carbonyl]-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-4-(1-furo[3,2-c]pyridin-2-yl-1-methylethyl)-xcex3-hydroxy-xcex1-(phenylmethyl)-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-4-(1-furo[3,2-c]pyridin-2-yl-1-methylethyl)-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(3,3,3-trifluoropropyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-4-(1-furo[3,2-c]pyridin-2-yl-1-methylethyl)-xcex3-hydroxy-2-[[(2,2,3,3,3-pentafluoropropyl)-mino]carbonyl]-xcex1-(phenylmethyl)-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-2-[[(2-fluoro-1,1-dimethylethyl)amino]carbonyl]-4-(1-furo[3,2-c]pyridin-2-yl-1-methylethyl)-xcex3-hydroxy-xcex1-(phenylmethyl)-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((1S,2R)-1,2-dihydro-2-hydroxy-1H-inden-1-yl)-4-(1-furo[3,2-c]pyridin-2-yl-1-methylethyl)-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((1S,2R)-1,2-dihydro-2-hydroxy-1H-inden-1-yl)-2-[[(2-fluoroethyl)amino]carbonyl]-4-[1-furo[3,2-c]pyridin-2-yl-1-methylethyl)-xcex3-hydroxy-xcex1-(phenylmethyl)-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((1S,2R)-1,2-dihydro-2-hydroxy-1H-inden-1-yl)-4-(1-furo[3,2-c]pyridin-2-yl-1-methylethyl)-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(3,3,3-trifluoropropyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((1S,2R)-1,2-dihydro-2-hydroxy-1H-inden-1-yl)-4-(1-furo[3,2-c]pyridin-2-yl-1-methylethyl)-xcex3-hydroxy-2-[[(2,2,3,3,3-pentafluoropropyl)amino]carbonyl-xcex1-(phenylmethyl)-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-4-(2-benzofuranylmethyl)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[5-(3-pyridinyl)-1-furanyl]methyl]-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-(3-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[5-(3-pyridinyl)-1-furanyl]methyl]-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[5-(5-pyrimidinyl)-1-furanyl]methyl]-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[(3-methyl-7-methoxy-4-benzofuranyl)methyl]-xcex1-(3-phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[(7-methoxy-2-benzofuranyl)methyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[(1-phenyl-1H-pyrrol-3-yl)methyl)-]-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[(1-phenyl-1H-imidazol-4-yl)methyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-4-(2-benzofuranylmethyl)-N-((1S,2R)-1,2-dihydro-2-hydroxy-1-inden-1-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((1S,2R)-1,2-dihydro-2-hydroxy-1H-inden-1-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-(3-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[(5-phenyl-2-furanyl)methyl]-xcex1-(3-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-4-(2-benzopyranylmethyl)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(3-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(3-pyridinylmethyl)-4-(thieno[2,3-b]thien-2-ylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-4-[(2,6-difluorophenyl)methyl]-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(3-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(3-pyridinylmethyl)-4-(thieno[3,2-b]thien-2-ylmethyl)-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[(7-methoxy-2-benzofuranyl)methyl]-xcex1-(3-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(3-pyridinylmethyl)-4-[[5-(2-thienyl)-2-furanyl]methyl]-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[(1-phenyl-1H-pyrrol-3-yl)methyl]-xcex1-(3-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-(1-phenyl-1H-imidazol-4-yl)methyl]-xcex1-(3-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[[5-(5-methyl-2-thienyl)-2-furanyl]methyl]-xcex1-(3-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[(5-phenyl-2-furanyl)methyl]-xcex1-(4-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl -1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-4-(2-benzofuranylmethyl)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(4-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[1-methyl-1-[5-(4-pyridinyl)-2-furanyl]ethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[1-[5-(4-pyridinyl)-1-furanyl]ethyl]-2-[[(2,2,2-trifluoroethyl-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[1-[5-(4-pyridinyl)-1-furanyl]ethyl]-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[1-methyl-1-(1-phenyl-1H-pyrazol-3-yl)ethyl]-xcex1-(3-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[1-methyl-1-(3-phenyl-5-isoxazolyl)ethyl]-xcex1-(3-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[1-methyl-1-(3-phenyl-5-isoxazolyl)ethyl]]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-4-[(7-chlorobenzofuran-2-yl)methyl]-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(3-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-4-(1-furo[3,2-c]pyridin-2-yl-1-methylethyl)-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2-difluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[5-(2-thiazolyl)-3-pyridinyl]methyl]-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[[5-(2-oxazolyl)-3-pyridinyl]methyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[5-(4-thiazolyl)-3-pyridinyl]methyl]-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[5-(2-thiazolyl)-2-furanyl]methyl]-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-4-[[5-(5-chloro-3-pyridinyl)-2-furanyl]methyl]-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[(5-phenyl-2-furanyl)methyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)4-[(4-chloro-5-phenyl-2-furanyl)methyl]-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[5-(2-pyridinyl)-2-furanyl]methyl]-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-4-[[5-(5-chloro-2-pyridinyl)-2-furanyl]methyl]-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[[5-(2-methyl-4-pyridinyl)-2-furanyl]methyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-4-[[(5-(2-ethyl-4-pyridinyl)-2-furanyl]methyl]-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[[5-(5-oxazolyl)-2-furanyl]methyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[1-(4-pyridinyl)-1H-pyrrol-3-yl]methyl]-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[1-(3-pyridinyl)-1H-pyrrol-3-yl]methyl]-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[5-(4-pyridazinyl)-2-furanyl]methyl]-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[1-methyl-1-[3-methyl-5-(4-pyridinyl)-2-furanyl]ethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[5-(2-pyrazinyl)-2-furanyl]methyl]-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[[5-(1-methyl-1H-pyrazol-4-yl)-3-pyridinyl]methyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[5-(2-thienyl)-3-pyridinyl]methyl]-2-[[(2,2,2-trifluoroethyl)amino]carbonyl-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[5-(3-thienyl)-3-pyridinyl]methyl]-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[5-(4-pyrimidinyl)-2-furanyl]methyl]-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-4-[(7-chlorofuro[3,2-c]pyridin-2-yl)methyl]-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[5-(3-pyridinyl)-2-oxazolyl]methyl]-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[5-(2-pyridinyl)-2-oxazolyl]methyl]-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[1-methyl]-1-[5-(2-pyridinyl)-2-oxazolyl]ethyl]-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[1-methyl-1-[5-(3-pyridinyl)-2-oxazolyl]ethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[(5-phenyl-2-furanyl)methyl]-xcex1-(5-pyrimidinylmethyl)-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[(5-phenyl-2-furanyl)methyl]-xcex1-(2-pyrazinylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1S,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[[5-(2-pyridinyl)-2-furanyl]methyl]-xcex1-(2-thienylmethyl)-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1S,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[[5-(5-pyrimidinyl)-2-furanyl]methyl]-xcex1-(5-thienylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1S,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[[5-(2-pyridinyl)-2-furanyl]methyl]-xcex1-(3-thienylmethyl)-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[(5-phenyl-2-furanyl)methyl]-xcex1-(2-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((1S,2R)-1,2-dihydro-2-hydroxy-1H-inden-1-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[5-(2-pyridinyl)-2-furanyl]methyl]-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-4-[[5-(5-chloro-2-pyridinyl)-2-furanyl]methyl]-N-((1S,2R)-1,2-dihydro-2-hydroxy-1H-inden-1-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[1-methyl-1-[5-(5-chloro-3-pyridinyl)-2-oxazolyl]ethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2 trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[1-methyl-1-[5-(5-chloro-2-pyridinyl)-2-oxazolyl]ethyl]-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[(3-chloro-1-phenyl-1H-pyrrol-3-yl)methyl]-xcex1-(3-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[(4-chloro-1-phenyl-1H-pyrrol-3-yl)methyl]-xcex1-(3-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[1-methyl-1-(1-phenyl-1H-triazoyl-4-yl)ethyl]-xcex1-(3-phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy4-[1-methyl-1-(1-phenyl-1H-triazoyl-4-yl)ethyl]-xcex1-(3-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-(4S-3,4-dihydro-1H-2,2-dioxobenzothiopyranyl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[5-(5-pyrimidinyl)-1-furanyl]methyl]-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-(4S-3,4-dihydro-1H-2,2-dioxobenzothiopyranyl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[5-(2-pyridinyl)-2-furanyl]methyl]-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[1-methyl-1-[5-(2-methyl-4-pyridinyl)-2-furanyl]ethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
and pharmaceutically acceptable salts thereof.
Also exemplifying the invention are compounds selected from the group consisting of
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-xcex3-hydroxy-4-[1-[5-(5-methoxy-3-pyridinyl)-2-oxazolyl]-1-methylethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-4-[5-(5-methyl-3-pyridinyl)-2-oxazolyl]-1-methylethyl]-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-4-[1-[5-(5-hydroxy-3-pyridinyl)-2-oxazolyl]-1-methylethyl]-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-4-[1-[5-[5-(difluoromethoxy)-3-pyridinyl]-2-oxazolyl]-1-methylethyl]-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-xcex1-(phenylmethylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-4-[1-[5-[5-(difluoromethyl)-3-pyridinyl]-2-oxazolyl]-1-methylethyl]-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-4-[1-[5-(2-fluorophenyl)-2-oxazolyl]-1-methylethyl]-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazine-pentanamide;
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-4-[1-[5-(3-fluorophenyl)-2-oxazolyl]-1-methylethyl]-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,yxcex3,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-4-[1-[5-(4-fluorophenyl)-2-oxazolyl]-1-methylethyl]-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-4-[1-[5-(5-ethoxy-3-pyridinyl)-2-oxazolyl]-1-methylethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-4-[1-[5-(5-fluoro-3-pyridinyl)-2-oxazolyl]-1-methylethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-4-[1-[5-(5-ethyl-3-pyridinyl)-2-oxazolyl]-1-methylethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy4-[1-methyl-1-[5-(5-propyl-3-pyridinyl)-2-oxazolyl]ethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-4-[1-methyl-1-[4-methyl-5-(3-pyridinyl)-2-oxazolyl]ethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-4-[1-[5-(5-methoxy-3-pyridinyl)-4-methyl-2-oxazolyl]-1-methylethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-4-[1-methyl-1-[5-[5-(methylthio)-3-pyridinyl]-2-oxazolyl]ethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-4-[1-[5-(5-dimethylamino-3-pyridinyl)-2-oxazolyl]-1-methylethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-4-[1-[3-(5-methoxy-3-pyridinyl)-5-isoxazoly]-1-methylethyl]-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-4-[1-[2-(5-methoxy-3-pyridinyl)-4-thiazolyl]-1-methylethyl]-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-4-[1-[2-(5-chloro-3-pyridinyl)-4-thiazolyl]-1-methylethyl]-N-[(3S,4)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-4-[1-[2-(3-pyridinyl)-4-thiazolyl]-1-methylethyl]-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-4-[1-[1-(5-methoxy-3-pyridinyl)-1H-pyrazol-3-yl]-1-methylethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-4-[1-[1-(5-chloro-3-pyridinyl)-1H-pyrazol-3-yl]-1-methylethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-4-[1-[1-(5-fluoro-3-pyridinyl)-1H-pyrazol-3-yl]-1-methylethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-4-[1-[1-(3-pyridinyl)-1H-pyrazol-3-yl]-1-methylethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1S,xcex3S,2S)-4-[1-[5-phenyl-2-oxazolyl]-1-methylethyl]-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex1-(furo[2,3-c]pyridin-2-ylmethyl)-xcex3-hydroxy-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1S,xcex3S,2S)-4-[1-[5-(4-chlorophenyl)-2-oxazolyl]-1-methylethyl]-N-[(3S,4)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex1-(furo[2,3-c]pyridin-2-ylmethyl)-xcex3-hydroxy-2-[[2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1S,xcex3S,2S)-4-[1-[5-(4-fluorophenyl)-2-oxazolyl]-1-methylethyl]-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex1-(furo[2,3-c]pyridin-2-ylmethyl)-xcex3-hydroxy-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1S,xcex3S,2S)-4-[1-[5-(4-chlorophenyl)-2-oxazolyl]-1-methylethyl]-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex1-(furo[2,3-c]pyridin-3-ylmethyl)-xcex3-hydroxy-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1S,xcex3S,2S)-4-[1-[5-(4-fluorophenyl)-2-oxazolyl]-1-methylethyl]-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex1-(furo[2,3-c]pyridin-3-ylmethyl)-xcex3-hydroxy-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1S,xcex3S,2)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-4-[1-[5-(4-fluorophenyl)-2-oxazolyl]-1-methylethyl]-xcex1-(furo[2,3-d]pyrimidin-6-ylmethyl)-xcex3-hydroxy-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
and pharmaceutically acceptable salts thereof.
A preferred aspect of the present invention is a compound selected from the group consisting of
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-4-(1-furo[3,2-c]pyridin-2-yl-1-methylethyl)-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[(5-phenyl-2-furanyl)methyl]-xcex1-(4-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S, 2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[1-methyl-1-(1-phenyl-1H-pyrazol-3-yl)ethyl]-xcex1-(3-pyridinylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-4-[[5-(2-pyridinyl)-2-furanyl]methyl]-2-[[(2,2,2-trifluoroethyl)-amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-4-[[5-(5-chloro-2-pyridinyl)-2-furanyl]methyl]-N-((3S,4S)-3,4dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-((3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl)-xcex3-hydroxy-4-[1-methyl-1-[5-(3-pyridinyl)-2-oxazolyl]ethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-4-[1-[5-(5-methoxy-3-pyridinyl)-2-oxazolyl]-1-methylethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy4-[1-[5-(5-fluoro-3-pyridinyl)-2-oxazolyl]-1-methylethyl]-xcex1-(phenylmethyl)-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1R,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex3-hydroxy-4-[1-[1-(5-fluoro-3-pyridinyl)-1H-pyrazol-3-yl]-1-methylethyl]-xcex1-(phenylmethyl)-2[[(2,2,2-trifluoromethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1S,xcex3S,2S)-4-[1-[5-(4-chlorophenyl)-2-oxazolyl]-1-methylethyl-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex1-(furo[2,3-c]pyridin-2-ylmethyl)-xcex3-hydroxy-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1S,xcex3S,2S)-4-[1-[5-(4-fluorophenyl)-2-oxazolyl]-1-methylethyl]-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex1-(furo[2,3-c]pyridin-2-ylmethyl)-xcex3-hydroxy-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1S,xcex3S,2S)-4-[1-[5-(4-chlorophenyl)-2-oxazolyl]-1-methylethyl]-N-(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex1-(furo[2,3-c]pyridin-3-ylmethyl)-xcex3-hydroxy-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1S,xcex3S,2S)-4-[1-[5-(4-fluorophenyl)-2-oxazolyl]-1-methylethyl]-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-xcex1-(furo[2,3-c]pyridin-3-ylmethyl)-xcex3-hydroxy-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
(xcex1S,xcex3S,2S)-N-[(3S,4S)-3,4-dihydro-3-hydroxy-2H-1-benzopyran-4-yl]-4-[1-[5-(4-fluorophenyl)-2-oxazolyl]-1-methylethyl]-xcex1-(furo[2,3-d]pyrimidin-6-ylmethyl)-xcex3-hydroxy-2-[[(2,2,2-trifluoroethyl)amino]carbonyl]-1-piperazinepentanamide;
and pharmaceutically acceptable salts thereof.
Other embodiments of the present invention include the following:
(a) A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier.
(b) A pharmaceutical composition made by combining a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier.
(c) The pharmaceutical composition of (a), wherein the composition further comprises a therapeutically effective amount of at least one AIDS treatment agent selected from the group consisting of AIDS antiviral agents, immunomodulators, and anti-infective agents.
(d) The pharmaceutical composition of (a), wherein the composition further comprises a therapeutically effective amount of at least one antiviral agent selected from the group consisting of non-nucleoside HIV reverse transcriptase inhibitors and nucleoside HIV reverse transcriptase inhibitors.
(e) The pharmaceutical composition of (d), further comprising a therapeutically effective amount of an additional HIV protease inhibitor.
(g) The pharmaceutical composition of (a), wherein the composition further comprises a therapeutically effective amount of at least one antiviral agent which is a CCR5 receptor antagonist.
(h) The pharmaceutical composition of (a), wherein the composition further comprises a therapeutically effective amount of at least one antiviral agent which is an HIV integrase inhibitor.
(i) The pharmaceutical composition of (a), further comprising a cytochrome P450 monooxygenase inhibitor (e.g., indinavir or ritonavir or a pharmaceutically acceptable salt thereof) in an amount effective to improve the pharmacokinetics of the compound.
(j) A method of inhibiting HIV protease in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of Formula (I).
(k) A method of preventing or treating infection by HIV in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of Formula (I).
(i) A method of treating AIDS in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of Formula (I).
(m) The method of (j) or (k) or (l), wherein the compound of Formula (I) is administered in combination with a therapeutically effective amount of at least one AIDS treatment agent selected from the group consisting of AIDS antiviral agents, immunomodulators, and anti-infective agents.
(n) The method of (j) or (k) or (l), wherein the compound of Formula (I) is administered in combination with a therapeutically effective amount of at least one antiviral agent selected from the group consisting of non-nucleoside HIV reverse transcriptase inhibitors and nucleoside HIV reverse transcriptase inhibitors.
(o) The method of (j) or (k) or (l), wherein the compound is administered in combination with a cytochrome P450 monooxygenase inhibitor in an amount effective to improve the pharmacokinetics of the compound.
(p) A method of inhibiting HIV protease in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any one of the compositions set forth in (a) to (i).
(q) A method of preventing or treating infection by HIV in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any one of the compositions set forth in (a) to (i).
(r) A method of treating AIDS in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any one of the compositions set forth in (a) to (i).
Additional embodiments of the invention include the pharmaceutical compositions and methods set forth in (a)-(r) above, wherein the compound employed therein is a compound of one of the embodiments, classes, or sub-classes of compounds described above.
The present invention also includes a process for preparing compounds of Formula (11): 
which comprises reacting a piperazine of Formula (III): 
with an aldehyde of formula R1xe2x80x94CHO in the presence of a reducing agent; wherein R1, R4, R5 and R6 are independently as defined above in Formula (I) or as defined in any embodiments, classes or aspects thereof. Suitable reducing agents include sodium cyanoborohydride, sodium triacetoxyborohydride, hydrogen plus a hydrogenation catalyst (e.g., a trasition metal catalystxe2x80x94such as Ni, Pt or Pdxe2x80x94or a compound thereofxe2x80x94such as a halide, hydroxide, or oxidexe2x80x94), zinc with HCl, sodium borohydride, iron pentacarbonyl with alcoholic KOH, and selenophenol (PhSeH). In one embodiment, the reducing agent is sodium cyanoborohydride or sodium triacetoxyborohydride.
The reaction is typically conducted in a solvent, which can be any inorganic or organic substance which can dissolve, disperse, and/or suspend the reactants and is chemically inert under the reaction conditions employed. Suitable solvents include C2-C4 nitriles (e.g., acetonitrile and propionitrile), N,N-di-C1-C6 alkyl tertiary amides of C1-C6 alkylcarboxylic acids (e.g., DMF and N,N-dimethylacetamide), C5-C6 cyclic tertiary amides (e.g., N-methylpyrrolidone), aliphatic C2-C6 ethers and di-ethers (e.g., ethyl ether, MTBE and dimethoxyethane), C4-C6 cyclic ethers and di-ethers (e.g., THF and dioxane), and combinations of two or more of the foregoing. In one embodiment, the solvent is an N,N-di-C1-C4 alkyl tertiary amide of a C1-C4 alkylcarboxylic acid. In another embodiment, the solvent is DMF, N,N-dimethylacetamide, or N-methylpyrrolidone.
The reaction temperature is suitably in a range of from about xe2x88x9220 to about 100xc2x0 C., and is typically in a range of from about xe2x88x9210 to about 80xc2x0 C. In one embodiment, the temperature is in a range of from about 0 to about 50xc2x0 C (e.g., from about 0 to about 30xc2x0 C.).
The relative amounts of reactants and reagents are typically selected so as to maximize the conversion of Compound III and the yield of Compound II. Accordingly, at least about one equivalent of aldehyde is typically employed per equivalent of Compound III. In one embodiment, the aldehyde is employed in an amount in the range of from about 1 to about 5 equivalents (e.g., from about 1 to about 1.5 equivalents) per equivalent of Compound II. The reducing agent is typically also employed in an amount of at least about one equivalent per equivalent of Compound III. In one embodiment, an equal number of equivalents of reducing agent and aldehyde are employed in the reaction.
In a typical procedure, Compound III and the aldehyde are dissolved in the solvent at a relatively low temperature (e.g., below about 5xc2x0 C.), followed by addition of the reducing agent, after which the reaction mixture is warmed to reaction temperature (e.g., from about 20 to about 25xc2x0 C.) and maintained at that temperature until the reaction is complete, as determined by a standard method of monitoring the progress of the reaction (e.g., HPLC). Compound II can then be recovered from the reaction mixture using conventional procedures such as filtration and washing of the precipitate. Yields of at least about 70% can be achieved by the process.
One embodiment of this process is a process for preparing compounds of Formula (II-A): 
which comprises reacting a piperazine of Formula (III-A): 
with an aldehyde of formula R1xe2x80x94CHO in the presence of a reducing agent; wherein R1, R4, R5 and R6 are independently as defined above in Formula (I) or as defined in any embodiments, classes or aspects thereof.
Another embodiment of this process is a process as set forth in the preceding paragraph, wherein: 
wherein X is O or S, and J is 
heterocycle, or substituted heterocycle; where
t is an integer from zero to 2;
each L is independently hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, fluorinated C1-C4 alkyl, or C1-C4 alkoxy;
heterocycle is 
substituted heterocycle is heterocycle as defined above having one or more substituents independently selected from halogen, C1-C4 alkoxy, C1-C4 alkyl, fluorinated C1-C4 alkoxy, fluorinated C1-C4 alkyl, xe2x80x94Sxe2x80x94CH3, xe2x80x94N(CH3)2, thiazolyl, and oxazolyl;
R4 is 
R5 is 
R6 is 
As used herein, the term xe2x80x9cC1-C6 alkylxe2x80x9d refers to a linear or branched chain alkyl group having from 1 to 6 carbon atoms, and is selected from the hexyl alkyl and pentyl alkyl isomers, n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. xe2x80x9cC1-C4 alkylxe2x80x9d refers to a linear or branched chain alkyl group having from 1 to 4 carbon atoms, and is selected from n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
The term xe2x80x9cC2-C6 alkenylxe2x80x9d refers to a linear or branched chain alkenyl group having from 2 to 6 carbon atoms, and is selected from the hexyl alkenyl and pentyl alkenyl isomers, 1-, 2- and 3-butenyl, 1- and 2-isobutenyl, 1- and 2-propenyl, and ethenyl. xe2x80x9cC2-C4 alkenylxe2x80x9d has an analogous definition.
The term xe2x80x9cC2-C6 alkynylxe2x80x9d refers to a linear or branched chain alkynyl group having from 2 to 6 carbon atoms, and is selected from the hexyl alkynyl and pentyl alkynyl isomers, 1-, 2- and 3-butynyl, 1- and 2-propynyl, and ethynyl. xe2x80x9cC2-C4 alkynylxe2x80x9d has an analogous definition.
The term xe2x80x9cC1-C6 alkoxyxe2x80x9d means an xe2x80x94Oxe2x80x94alkyl group wherein alkyl is C1 to C6 alkyl as defined above. xe2x80x9cC1-C4 alkoxyxe2x80x9d has an analogous meaning; i.e., it is an alkoxy group selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and sec-butoxy. Similarly, xe2x80x9cC1-C3 alkoxyxe2x80x9d is selected from methoxy, ethoxy, n-propoxy, and isopropoxy.
The term xe2x80x9cC3-C6 cycloalkylxe2x80x9d refers to a cyclic ring selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. xe2x80x9cC3-C5 cycloalkylxe2x80x9d has an analogous meaning.
The term xe2x80x9cC3-C6 azacycloalkylxe2x80x9d refers to a saturated monocyclic group consisting of one nitrogen and from 3 to 6 carbon atoms, selected from azetidinyl (i.e., azacyclobutyl), pyrrolidinyl (azacyclopentyl), piperidinyl (azacyclohexyl), and hexahydroazepinyl (azacycloheptyl). xe2x80x9cC3-C5 azacycloalkylxe2x80x9d has an analogous meaning.
The term xe2x80x9chalogenxe2x80x9d (which may alternatively be referred to as xe2x80x9chaloxe2x80x9d) refers to fluorine, chlorine, bromine and iodine (alternatively, fluoro, chloro, bromo, and iodo).
The term xe2x80x9cfluorinated C1-C6 alkylxe2x80x9d (which may alternatively be referred to as xe2x80x9cC1-C6 fluoroalkylxe2x80x9d) means a C1-C6 alkyl group as defined above with one or more fluorine substituents. The term xe2x80x9cfluorinated C1-C4 alkylxe2x80x9d has an analogous meaning. Representative examples of suitable fluoroalkyls include the series (CH2)0-3CF3 (i.e., trifluoromethyl; 2,2,2-trifluoroethyl; 3,3,3-trifluoro-n-propyl, etc.), 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 3,3,3-trifluoroisopropyl, 1,1,1,3,3,3-hexafluoroisopropyl, and perfluorohexyl.
The term xe2x80x9cfluorinated C1-C6 alkoxyxe2x80x9d (which may alternatively be referred to as xe2x80x9cC1-C6 fluoroalkoxyxe2x80x9d) means a C1-C6 alkoxy group as defined above wherein the alkyl moiety has one or more fluorine substituents. The terms xe2x80x9cfluorinated C1-C4 alkoxyxe2x80x9d and xe2x80x9cfluorinated C1-C3 alkoxyxe2x80x9d have analogous meanings. Representative examples include the series O(CH2)0-3CF3 (i.e., trifluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoro-n-propoxy, etc.), 1,1,1,3,3,3-hexafluoroisopropoxy, and so forth.
The term xe2x80x9ccarbocyclicxe2x80x9d (which may alternatively be referred to as xe2x80x9ccarbocyclexe2x80x9d) refers to a saturated or unsaturated monocyclic ring consisting of from 5 to 7 carbon atoms or a saturated or unsaturated bicyclic ring consisting of from 7 to 10 carbon atoms. It is understood that either or both rings of the bicyclic may be saturated or unsaturated. Exemplary carbocyclics include, but are not limited to, cyclopentyl, cyclohexyl, cylcoheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, naphthyl, tetrahydronaphthyl (tetralin), indenyl, and indanyl.
The term xe2x80x9carylxe2x80x9d refers to aromatic mono- and poly-carbocyclic ring systems, wherein the carbocyclic rings in the polyring systems may be fused or attached to each other via a single ring carbon. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, and biphenylenyl.
The term xe2x80x9csubstituted arylxe2x80x9d refers to an aryl group as defined above having one or more substituents independently selected from cyano, halo, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, fluorinated C1-C6 alkyl, fluorinated C1-C6 alkoxy, heterocycle, substituted heterocycle, and the like.
The term xe2x80x9cheterocyclicxe2x80x9d (which may alternatively be referred to as xe2x80x9cheterocyclexe2x80x9d) refers to (i) a 4- to 8-membered, saturated or unsaturated monocyclic ring consisting of carbon atoms and one or more heteroatoms selected from N, O and S or (ii) a 7- to 10-membered bicyclic ring system, either ring of which is saturated or unsaturated, consisting of carbon atoms and one or more heteroatoms selected from N, O and S; and wherein the nitrogen and sulfur heteroatoms in (i) or (ii) are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. The heterocyclic ring may be attached at any heteroatom or carbon atom, provided that attachment results in the creation of a stable structure. Representative examples of heterocyclic groups include azetidinyl, piperidinyl, piperazinyl, azepinyl, pyrrolyl, indazolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, imidazolinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, quinoxazolinyl, isothiazolidinyl, methylenedioxyphenyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadazolyl, benzopyranyl, benzothiazolyl, benzoazolyl, furyl, tetrahydrofuryl, benzofuranyl, benzothiofuranyl, azabenzofuranyl, benzothiazolyl, azabenzothiazolyl, azabenzoxazolyl, tetrahydropuranyl, thiophenyl (alternatively referred to herein as xe2x80x9cthienylxe2x80x9d), thienothiophenyl, benzothiophenyl, and oxadiazolyl.
The term xe2x80x9csubstituted heterocyclicxe2x80x9d (alternatively xe2x80x9csubstituted heterocyclexe2x80x9d) refers to a heterocyclic group as defined above having one or more substituents independently selected from cyano, halo, hydroxy, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C3-C6 azacycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, fluorinated C1-C6 alkyl, fluorinated C1-C6 alkoxy, aryl (e.g., phenyl), and the like.
The term xe2x80x9cheteroarylxe2x80x9d refers to a heterocyclic group as defined above, wherein the monocyclic ring (i) is an aromatic ring and in the bicyclic ring system (ii) at least one ring is an aromatic ring. In one aspect, heteroaryl refers to (i) a 5- or 6-membered aromatic ring consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, S, and O or (ii) an 8- to 10-membered bicyclic ring system consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, S, and O wherein at least one of the rings in the bicyclic system is an aromatic ring.
The term xe2x80x9csubstituted heteroarylxe2x80x9d refers to a heteroaryl group as defined above having one or more substituents independently selected from cyano, halo, hydroxy, amino, C1-C4 alkylamino, (di-(C1-C4 alkyl)amino, C3-C6 azacycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, fluorinated C1-C6 alkyl, fluorinated C1-C6 alkoxy, aryl (e.g., phenyl), substituted aryl, heterocycle, and substituted heterocycle.
The term xe2x80x9csubstitutedxe2x80x9d includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution is chemically allowed and results in a chemically stable compound.
The symbol xe2x80x9cxe2x80x9d in front of an open bond in the structural formula of a group marks the point of attachment of the group to the rest of the molecule.
When any variable or term occurs more than one time in any constituent or formulas set forth herein (e.g., Formula (I)), its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if R2 and R3 in Formula (I) are both designated as xe2x80x9cC1-C4 alkylxe2x80x9d, R2 and R3 can represent the same or different alkyl groups embraced by the term. As another example, in an embodiment of Formula (I) in which R1 and R4 are both heteroaryl, R1 and R4 can be the same or different heteroaryl groups.
Combinations of substituents and/or variables are permitted only to the extent such combinations result in stable compounds.
The present invention includes pharmaceutical compositions useful for inhibiting HIV protease, comprising an effective amount of a compound of this invention, and a pharmaceutically acceptable carrier. Pharmaceutical compositions useful for preventing or treating infection by HIV, or for treating AIDS or ARC, are also encompassed by the present invention, as well as a method of inhibiting HIV protease, and a method of preventing or treating infection by HIV, or of treating AIDS or ARC. An aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of an agent useful for treating HIV infection and/or AIDS (alternatively referred to as an HIV/AIDS treatment agent) selected from:
(1) an HIV/AIDS antiviral agent,
(2) an anti-infective agent, and
(3) an immunomodulator.
The present invention also includes the use of a compound of the present invention as described above as a medicament for (a) inhibiting HIV protease, (b) preventing or treating infection by HIV, or (c) treating AIDS or ARC. The present invention further includes the use of a compound of the present invention as described above in the preparation of a medicament for (a) inhibiting HIV protease, (b) preventing or treating infection by HIV, or (c) treating AIDS or ARC.
The present invention also includes the use of any of the HIV protease inhibiting compounds of the present invention as described above in combination with one or more HIV/AIDS treatment agents selected from an HIV/AIDS antiviral agent, an anti-infective agent, and an immunomodulator for use as a medicament for (a) inhibiting HIV protease, (b) preventing or treating infection by HIV, or (c) treating AIDS or ARC, said medicament comprising an effective amount of the HIV protease inhibitor compound and an effective amount of the one or more treatment agents.
The present invention further includes the use of any of the HIV protease inhibiting compounds of the present invention as described above in combination with one or more HIV/AIDS treatment agents selected from an HIV/AIDS antiviral agent, an anti-infective agent, and an immunomodulator for the manufacture of a medicament for (a) inhibiting HIV protease, (b) preventing or treating infection by HIV, or (c) treating AIDS or ARC, said medicament comprising an effective amount of the HIV protease inhibitor compound and an effective amount of the one or more treatment agents.
The compounds of the present invention may have asymmetric centers and may occur, except when specifically noted, as mixtures of stereoisomers or as individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention.
A therapeutically effective amount of the compounds of the present invention are useful in the inhibition of HIV protease, the prevention or treatment of infection by human immunodeficiency virus (HIV) and the treatment of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by e.g., blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery. The compounds of the invention can also be used in xe2x80x9csalvagexe2x80x9d therapy; i.e., the compounds can be used to treat HIV infection, AIDS, or ARC in HIV-positive subjects whose viral load achieved undetectable levels via conventional therapies employing known protease inhibitors, and then rebounded due to the emergence of HIV mutants resistant to the known inhibitors.
The compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV protease, e.g., by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes.
The present invention also provides for the use of a compound of structural formula (I) to make a pharmaceutical composition useful for inhibiting HIV protease and in the treatment of AIDS or ARC.
The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to all acceptable salts of the compounds of Formula (I) (in the form of water- or oil-soluble or dispersible products) and includes the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of acid addition salts include acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as ethylenediamine, N-methyl-glutamine, N,Nxe2x80x2-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, choline, N-benzylphenethyl-amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and dicyclohexylamine, and salts with amino acids such as arginine, lysine, ornithine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates such as dimethyl, diethyl, dipropyl, dibutyl, and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides, and iodides; and aralkyl halides such as benzyl and phenethyl bromides and others. The salt can be used as a dosage form for modifying the solubility or hydrolysis characteristics of the compound or can be used in sustained release or pro-drug formulations.
Also, pharmaceutically acceptable esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
For these purposes, the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
The term xe2x80x9cadministrationxe2x80x9d and variants thereof (e.g., xe2x80x9cadministeringxe2x80x9d a compound) in reference to a compound of the invention each mean providing the compound or a prodrug of the compound to the individual in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., AIDS antivirals), xe2x80x9cadministrationxe2x80x9d and its variants are each understood to include concurrent and sequential provision of the compound or prodrug thereof and other agents.
Thus, in accordance with the present invention there is further provided a method of treating and a pharmaceutical composition for treating HIV infection and AIDS. The treatment involves administering to a subject in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of the present invention.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The expression xe2x80x9cpharmaceutically acceptablexe2x80x9d means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The term xe2x80x9csubject,xe2x80x9d (alternatively referred to herein as xe2x80x9cpatientxe2x80x9d) as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
These pharmaceutical compositions may be in the form of orally-administrable suspensions or tablets, nasal sprays, sterile injectible preparations, for example, as sterile injectible aqueous or oleagenous suspensions or suppositories.
When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing-agents known in the art.
The injectible solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer""s solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
The compounds of this invention can be administered orally to humans in a dosage range of 0.01 to 1000 mg/kg body weight in divided doses. One preferred dosage range is 0.1 to 200 mg/kg body weight orally in divided doses. Another preferred dosage range is 0.5 to 100 mg/kg body weight orally in divided doses. For oral administration, the compositions are preferably provided in the form of tablets containing 1 to 1000 milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
The present invention is also directed to combinations of the HIV protease inhibitor compounds with one or more agents useful in the treatment of HIV infection and/or AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the HIV/AIDS antivirals, imunomodulators, antiinfectives, or vaccines, such as those in Table 1 as follows:
It will be understood that the scope of combinations of the compounds of this invention with HIV/AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in Table 1 above, but includes in principle any combination with any pharmaceutical composition useful for the treatment of HIV infection and/or AIDS.
One suitable combination is a compound of the present invention and a nucleoside inhibitor of HIV reverse transcriptase such as AZT, 3TC, ddC, or ddI. Another suitable combination is a compound of the present invention and a non-nucleoside inhibitor of HIV reverse transcriptase, such as efavirenz, and optionally a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI.
Still another suitable combination is any one of the combinations in the preceding paragraph, further comprising an additional HIV protease inhibitor such as indinavir, Compound A, nelfinavir, ritonavir, saquinavir, amprenavir, or abacavir. An aspect of this combination is the combination wherein the additional inhibitor of HIV protease is the sulfate salt of indinavir. Another aspect of this combination is the combination in which the additional protease inhibitor is selected from nelfinavir and ritonavir. Still another aspect of this combination is the combination in which the additional inhibitor of HIV protease is saquinavir, which is typically administered in a dosage of 600 or 1200 mg tid.
Other suitable combinations include a compound of the present invention with the following (1) efavirenz, optionally with AZT and/or 3TC and/or ddI and/or ddC, and optionally with indinavir; (2) any of AZT and/or ddI and/or ddC and/or 3TC, and optionally with indinavir; (3) d4T and 3TC and/or AZT; (4) AZT and 3TC; and (5) AZT and d4T.
Another aspect of the present invention is co-administration of a compound of the present invention with an inhibitor of cytochrome P450 monooxygenase in an amount effective to improve the pharmacokinetics of the compound. Compounds of the invention can be metabolized, at least in part, by cytochrome P450 (CYP3A4). Co-administration of compounds of the invention with a cytcochrome P450 inhibitor can improve the pharmacokinetic profile of the compound in subjects (e.g., humans); i.e., co-administration can increase Cmax (the maximum plasma concentration of the compound), AUC (area under the curve of plasma concentration of the compound versus time), and/or the half-life of the compound. Suitable P450 inhibitors include, but are not limited to, indinavir and ritonavir. It is to be understood that the primary role of indinavir and ritonavir in this circumstance is as a pharmacokinetic modulator and not as a protease inhibitor; i.e., an amount of indinavir or ritonavir which is effective for improving the pharmacokinetics of the compound can provide a secondary or even negligible contribution to the antiviral effect. Improvements in the pharmacokinetic profile have been observed for compounds of the present invention, when co-dosed with P450-inhibiting amounts of either ritonavir or indinavir.
A compound of the present invention can also be administered in combination with an HIV integrase inhibitor such as a compound described in WO 99/62520, WO 99/62513, or WO 99/62897. A compound of the present invention can also be administered in combination with a CCR5 receptor antagonist, such as a compound described in WO00/59502 or WO 00/59503.
In the above-described combinations, the compound of the present invention and other active agents may be administered together or separately. In addition, the administration of one agent may be prior to, concurrent with, or subsequent to the administration of other agent(s). These combinations may have unexpected or synergistic effects on limiting the spread and degree of infection of HIV.
Efavirenz is (xe2x88x92)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, also known as DMP-266 or SUSTIVA(copyright) (DuPont) or STOCRIN(copyright) (Merck). Efavirenz and its utility as an HIV reverse transcriptase inhibitor is described in U.S. Pat. No. 5,519,021 and in the corresponding PCT published application, WO 95/20389. Efavirenz can be synthesized by the protocol of U.S. Pat. No. 5,633,405. Additionally, the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition and cyclization sequence is described in Thompson et al., Tetrahedron Letters 1995, 36: 8937-40, as well as in the PCT publication, WO 96/37457.
AZT is 3xe2x80x2-azido-3xe2x80x2-deoxythymidine, is also known as zidovudine, and is available from Burroughs-Wellcome under the tradename RETROVIR(copyright). Stavudine is 2xe2x80x2,3xe2x80x2-didehydro-3xe2x80x2-deoxythymidine, is also known as 2xe2x80x2,3xe2x80x2-dihydro-3xe2x80x2-deoxythymidine and d4T, and is available from Bristol-Myers Squibb under the tradename ZERIT(copyright). 3TC is (2R-cis)-4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone, is also known as (xe2x88x92)-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine and lamivudine, and is available from Glaxo Wellcome under the tradename EPIVIR(copyright). ddC is 2xe2x80x2,3xe2x80x2-dideoxycytidine, is also known as zalcitabine, and is available from Hoffman LaRoche under the tradename HIVID(copyright). ddI is 2xe2x80x2,3xe2x80x2-dideoxyinosine, is also known as didanosine, and is available from Bristol-Myers-Squibb under the tradename VIDEX(copyright). The preparation of ddC, ddI and AZT are also described in EPO 0,484,071.
Indinavir is N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-Nxe2x80x2-(t-butylcarboxamido)-piperazinyl))pentaneamide, and can be prepared as described in U.S. Pat. No. 5,413,999. Indinavir is generally administered as the sulfate salt at a dosage of 800 mg three times a day. Indinavir sulfate is available from Merck under the tradename CRIXIVAN(copyright).
Compound A is N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(2-benzo[b]furanylmethyl)-2(S)-Nxe2x80x2-(t-butylcarboxamido)piperazinyl))pentaneamide, preferably administered as the sulfate salt. Compound A can be prepared as described in U.S. Pat. No. 5,646,148.
Ritonavir is [5S-(5R*,8R*,10R*, 11R*)]-10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid 5-thiazolylmethyl ester, also known as 5-thiazolylmethyl [(aS)-a-[(1S,3S)-1-hydroxy-3-[(2S)-2-[3-[(2-isopropyl-4-thiazolyl)methyl]-3-methylureido]-3-methylbutyramido]-4-phenylbutyl]phenethyl]carbamate. It is available from Abbott under the tradename NORVIR(copyright). Ritonavir can be prepared as described in U.S. Pat. No. 5,484,801.
Nelfinavir is [3S-[2(2S*,3S*),3a,4ab,8ab]]-N-(1,1-dimethylethyl)decahydro-2-[2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]-3-isoquinolinecarboxamide, also known as (3S,4aS,8aS)-N-tert-Butyl-2-[(2R,3R)-3-(3,2-crestoamido)-2-hydroxy-4-(phenylthio)butyl]decahydro-3-isoquinolinecarboxamide. VIRACEPT(copyright), the monomethanesulfonate salt of nelfinavir (nelfinavir mesylate) is commerically available from Agouron. Nelfinavir can be prepared as described in U.S. Pat. No. 5,484,926.
Saquinavir is N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS ,8aS)-isoquinoline-3(S)-carboxamide. Saquinavir can be prepared in accordance with procedures disclosed in U.S. Pat. No. 5,196,438. INVIRASE(copyright) (saquinavir mesylate) is available from Roche Laboratories.
Amprenavir is 4-amino-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide, also known as Compound 168 and 141 W94. Amprenavir is an aspartyl protease inhibitor that can be prepared by following the procedures described in U.S. Pat. No. 5,585,397. Amprenavir is available under the tradename AGENERASE(copyright) from Glaxo Wellcome. Amprenavir can be prepared as described in U.S. Pat. No. 5,783,701.
Abacavir is (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol, also known as 1592U89. Abacavir can be prepared by following the protocol of EP 0434450.
Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows:
Alloc=allyloxycarbonyl
AcOH=acetic acid
BOC or Boc=t-butyloxycarbonyl
BOC-ON=2-(tert-butoxycarbonylamino)-2-phenyl acetonitrile
Bu=butyl
CBZ=carbobenzoxy (alternatively, benzyloxycarbonyl)
CSA=camphorsulfonic acid
DCE=dichloroethane
DCM=dichloromethane
DMF=dimethylformamide
DMSO=dimethylsulfoxide
DIEA=diisopropylethylamine
EDC=1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
ES=electron spray (ionization)
Et=ethyl
Et2O=diethyl ether
EtOAc=ethyl acetate
EtOH=ethanol
HBTU=1-hydroxybenzotriazole
HOAT=1-hydroxy-7-azabensotriazole
HOBT=1-hydroxy benzotriazole hydrate
HPLC=high performance liquid chromatography
IPA=isopropyl alcohol
KF=Karl Fisher titration for water
LC=liquid chromatography
Me=methyl
MeOH=methanol
MS=mass spectrometry
NMP=N-methyl pyrrolidinone
NMR=nuclear magnetic resonance
Pd(dppf)Cl2=1,1xe2x80x2-bis(diphenylphosphino)ferrocene palladium dichloride
Ph=phenyl
TBAF=tetrabutylammonium fluoride
TBSCl=t-butyldimethylsilyl chloride
TBSOTf=t-butyldimethylsilyl triflate
TEA=triethylamine
TFA=trifluoroacetic acid
TFEA=trifluoroethylamine
Tf2O=triflic anhydride
THF=tetrahydrofuran
TLC=thin layer chromatgraphy
TMEDA=N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine
TMSCN=trimethylsilyl cyanide
TsOH=p-toluenesulfonic acid
The compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.
The preparation of the compounds of the present invention can be carried out in sequential or convergent synthetic routes, as shown in Schemes 1-8 below. A compound of Formula (I) can be prepared in accordance with Scheme 1, wherein Compound I is readily prepared via literature procedures described in Dorsey et al., J. Med. Chem. 1994, 37: 3443-3451, and also in U.S. Pat. No. 5,413,999. Treatment of the hydroxyl compound 1 with triflic anhydride and lutidine in an inert solvent such as dichloromethane provides triflate 2. Displacement of the triflate with piperazine 3 occurs on heating in an inert solvent such as isopropanol to give lactone 4. Hydrolysis of lactone 4 with an aqueous lithium hydroxide provides the hydroxy acid which is conveniently protected with a standard silyl protecting group such as t-butyldimethylsilyl by reaction with either t-butyldimethylsilyl chloride in the presence of imidazole in an inert solvent or the reaction with the silyl triflate and diisopropyl ethylamine in an inert solvent such as dichloromethane. Mild aqueous hydrolysis of the silyl ester provides the protected hydroxy-acid 5. Amide coupling of compound 5 with NH2R5 to obtain 6 is typically performed by the carbodiimide method with reagents such as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and HOBT in an inert solvent such as dichloromethane. Other methods of forming the amide or peptide bond include, but are not limited to, the synthetic routes via an acid chloride, azide, mixed anhydride or activated ester. The silyl protecting group is removed with fluoride to arrive at compound 7. The BOC protecting group on the amine is then removed with a strong acid such as trifluoroacetic acid or hydrochloric acid in an alcoholic solvent such as methanol to give the penultimate intermediate 8. Penultimate 8 is then reacted with the desired aldehyde 9 and a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in an inert solvent such as dichloromethane to give compound 10. 
A more convergent route to compounds of the present invention is presented in Scheme 2, below. The orthogonally protected piperazine 11 can be selectively deprotected. The BOC protecting group can be removed by treatment with strong acids such as trifluoroacetic acid in dichloromethane or HCl in methanol. The resulting amine 12 can then be reacted with an aldehyde in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride to give piperazine 13. Removal of the Alloc protecting group is readily accomplished with a palladium catalyst in the presence of a nucleophilic trapping agent such as 1,3-dimethylbarbituric acid or as in J. Org. Chem. 1993, 58, 6109-6113. Displacement of the triflate of 2 with piperazine 14, as in Scheme 1 gives lactone 15 which is then converted into compounds of the present invention following the route depicted in Scheme 1. 
An alternative route to the instant compounds is presented in Scheme 3, as exemplified for NH2R5=aminoindanol. Compound 16 can be easily prepared according to the procedures described in the literature including, but not limited to, those described in Tetrahedron Letters 1995, 36: 2195-2198 and U.S. Pat. No. 5,646,148. As shown in Part A of Scheme 3, the epoxide opening can be carried out by heating piperazine 3 and the epoxide in an inert solvent. Acidic removal of the protecting groups can be accomplished by treatment with hydrochloric acid in an alcoholic solvent such as methanol, ethanol or isopropanol. The resulting intermediate 18 is then reductively aminated as in Scheme 1 to provide the compounds of the present invention. Alternatively, as shown in Part B of Scheme 3, the epoxide opening can be preformed with fully elaborated piperazine 14 to give 20. Once again the protecting group is removed with strong acid to give 19. 
Intermediates of formula NH2R5 can be readily prepared via the literature procedures including, but not limited to, those found in Tetrahedron Letters 1991 32: 711-714, Tetrahedron Letters 1995, 36: 3993-3996 and Synthesis 1998, 938-961. A procedure for preparing cis-aminochromanols by the stereoselective hydroge bromide-promoted hydrogenation of an xcex1-hydroxyoxime is described in Davies et al., Tetrahedron Letters 2000, 41: 8021-8025.
Piperazine intermediates are readily prepared from the known piperazine carboxylic acid 21, which can be prepared as described in Hel. Chem. Acta. 1960, 43: 888-896. Selective monoprotection of the piperazine is carried out using BOC anhydride as described in Tetrahedron Letters 1989, 30: 5193-5196. The remaining unprotected amine can then be protected with any number of chloroformates including allyl chloroformate or benzyl chloroformate to give 23. Amide couplings of 23 with NH2R6 to give 24 are performed using standard amide coupling reactions as described above. Many NH2R6 amines are commercially available and others can be prepared via literature methods including, but not limited to, those described in Tetrahedron Letters 1999, 40, 3831-3834. Acidic removal of the BOC protecting group as before gives 25. The Alloc group can be removed as before. The CBZ group is readily removed by hydrogenolysis with a palladium catalyst under a hydrogen atmosphere in an alcoholic solvent such as methanol or ethanol. Removal of the protecting groups can also be accomplished by a number of methods known in the art, such as those described in Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991. These deprotected intermediates are then carried onto compounds of the instant invention via the synthetic routes shown in Schemes 1, 2 and 3. 
The desired aldehyde intermediates are, in many cases, commercially available (e.g., Aldrich Chemical). Other aldehydes of interest can be prepared by literature methods including classical methods familiar to those skilled in the art. Stille and Suzuki coupling of commercially and readily available aryl and heteroaryl halides, aryl trialkylstannanes, and arylboronic acids also provides the desired aldehydes as exemplified for bromofuran in Scheme 5 below. Aldehyde 27 can be reacted with trialkylarylstannane 26 in the presence of a palladium catalyst by the method of Gronowitz et al., J. Heterocyclic Chem. 1995, 35: 771, to give 28. Alternatively, trialkylstannane 30 can be coupled with arylhalides such as 29 to give 31 which can be deprotected under mild conditions with dilute hydrochloric acid to give aldehyde 28. Other aldehydes are available via metal halogen exchange followed by anion quenching with DMF as described by Vogel et al., J. Chem. Soc. Perkin Trans I, 1974, 37. Metalation of a biaryl or heterobiaryl compound such as 32 with a strong base such as n-butyllithium at low temperature in an inert solvent such as THF followed by anion trapping with DMF also provides aldehydes such as 28. 
When R2 and R3 are alkyl, the necessary intermediates can be formed as shown in Scheme 6 below. Piperazine 12 can be treated with TMSCN and a ketone in acetic acid to give intermediate 34 according to the method described in J. Org. Chem. 1990, 55, 4207-4209. The Alloc protecting group is removed as described in Scheme 4 and the resulting intermediate, 35, is then treated with an excess of a Grignard to give the gem-dialkyl compound 14A. This intermediate is then converted to the compounds of the present invention via chemistry described in Schemes 2 and 3 above. 
An additional route to intermediates such as 14A, where R2 and R3 are alkyl or cycloalkyl, is depicted in Scheme 7, below. Alkylation of piperazine 25, where Pxe2x80x2 is an appropriate protecting group such as those described above, with alkylating agent 36, is conveniently carried out in the presence of copper oxide, copper, and a tertiary amine base according to methods described in J. Org. Chem 1996, 61: 6517-6522, J. Am. Chem. Soc. 1960, 4908, and J. Org. Chem. 1994, 59: 2282-2284, where R2 and R3 are alkyl or cycloalkyl and X is a leaving group such as bromine, chlorine, mesylate, triflate, or phosphonate. Heterocycles of interest can be prepared from the acetylenic piperazine 37 using chemistry known to those skilled in the art. For example, intermediates such as 39 can be formed by the reaction of iodo or bromo phenols such as 38 with 37 according to the procedures of Castro et al., J. Org. Chem. 1966, 31: 4071-4078, Larock et al., J. Org. Chem. 1995, 60: 3270, or Arcadi et al., Synthesis 1986, 749. Triazole intermediates 41 are readily available from the reaction of 37 and aryl or heteroaryl azides as shown for phenylazide 40 in an inert high boiling solvent such as dichlorobenzene according to the method of Sakamoto et. al. as described in Heterocycles 1993, 35: 1273. Sydnones, such as 42, are available by procedures detailed in J. Heterocycl. Chem. 1992, 29: 1013-1015. They can be reacted with 37 to give pyrazoles such as 43 according to the procedure of Gotthardt et al. as described in Chem. Ber. 1968, 101: 536. Isoxazole intermediates such as 45 can be formed by treatment of the piperazine 37 with nitrones like 44 in a high boiling solvent such as nitrobenzene as described in Liebigs Ann. Chem. 1992, 947-952. Each of these piperazine intermediates can be converted to compounds of the instant invention via chemistry depicted in Schemes 1-3 above. 
Oxazolyl piperazine intermediates such as 50 are available via the route shown in Scheme 8 below. Alkylation of piperazine 25 with bromo acid 46 in the presence of silver triflate in an inert solvent such as THF, according to methods detailed in J. Org. Chem. 1995, 60: 4013-4016, provides 47. Amide coupling of amine 48 to acid 47 to provide 49 can be carried out by any of the methods described above including the EDC/HOBT method. Amines such as 48 are prepared via chemistry described in Org. Synth. 1986, 64: 19-26 and Tetrahedron Letters 1999, 40: 6739-6743. Oxazole formation is accomplished by the action of a strong acid such as sulfuric acid on 49 in an inert solvent at elevated temperature, or as described in J. Med. Chem. 1996, 39: 2753-2763, to give intermediate 50. Again, intermediates such as these can be transformed into compounds of the instant invention via synthetic routes shown in Schemes 1,2, and 3. 
The present invention also includes a process for preparing a nitrogen-protected piperazine carboxamide of Formula (I*): 
wherein the process comprises:
(A) hydrogenating a pyrazine carboxamide of Formula (II*): 
xe2x80x83in a solvent to obtain the corresponding piperazine carboxamide of Formula (III*): 
(B) resolving the S-carboxamide isomer of Compound III* by:
(b1) forming a solution comprising Compound III*, a chiral acid, and solvent;
(b2) crystallizing from the solution a salt which contains predominantly either the S- or R-isomer;
(b3) if the precipitated salt crystals consist predominantly of the desired isomer, separating the salt crystals from the mother liquor; and
(b4) if the mother liquor consists predominantly of the desired isomer, separating the salt crystals from the mother liquor and recovering the isomer from the mother liquor; and
(C) breaking the separated crystalline salt of the S-carboxamide isomer by treating the salt with base, and treating the free S-isomer with a nitrogen-protecting agent to obtain piperazine amide (I*); wherein
P is a nitrogen-protecting group;
R6A is hydrogen, C1-C6 alkyl or fluorinated C1-C6 alkyl; and
each of Rs, Rt and Ru is independently hydrogen, C1-C4 alkyl, xe2x80x94C(xe2x95x90O)Rw, xe2x80x94COORw, or xe2x80x94C(xe2x95x90O)NRwRz, where Rw and Rz are each independently hydrogen or C1-C4 alkyl.
The piperazine carboxamides of Formula I* are useful as intermediates in the preparation of compounds of the invention as described above. In this process, the group R6A in Compounds I*, II*, and III* is hydrogen, C1-C6 alkyl or fluorinated C1-C6 alkyl. In one embodiment, R6A is hydrogen, C1-C4 alkyl or fluorinated C1-C4 alkyl. In another embodiment, R6A is C1-C4 alkyl (e.g., methyl, ethyl, isopropyl, t-butyl, and so forth). In an aspect of the preceding embodiment, R6A is t-butyl.
In still another embodiment, R6A is fluorinated C1-C6 alkyl. In an aspect of the preceding embodiment, R6A is 
In another aspect of the preceding embodiment R6A is 
In the process, each of Rs, Rt and Ru is independently hydrogen, C1-C4 alkyl, xe2x80x94C(xe2x95x90O)Rw, xe2x80x94COORw, or xe2x80x94C(xe2x95x90O)NRwRz, where Rw and Rz are each independently hydrogen or C1-C4 alkyl. In one embodiment, one of Rs, Rt and Ru is hydrogen, C1-C4 alkyl, xe2x80x94C(xe2x95x90O)Rw, xe2x80x94COORw, or xe2x80x94C(xe2x95x90O)NRwRz, and the other two of Rs, Rt and Ru is hydrogen. In another embodiment, each of Rs, Rt and Ru is hydrogen.
P in Compound I* is a nitrogen-protecting group. Suitable protective groups and methods for protecting nitrogen via these groups include those described in Protective Groups in Organic Chemistry, J. F. W. McOmie, editor, Plenum Press, 1973; Theodora W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1985; and W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991.
In one embodiment, P is: (a) (C1-C4 alkyl)-oxycarbonyl, (b) (C3-C8 cycloalkyl)-oxycarbonyl, (c) benzyloxycarbonyl in which the benzyl is optionally substituted with 1 or 2 substituents independently selected from C1-C4 alkyl, xe2x80x94Oxe2x80x94C1-C4 alkyl, and halo, (d) benzyl optionally substituted with 1 or 2 substituents independently selected from C1-C4 alkyl, xe2x80x94Oxe2x80x94C1-C4 alkyl, and halo, (e) trihaloacetyl, or (f) tri-(C1-C4 alkyl)silyl. Exemplary protecting groups include t-butyloxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, trifluoroacetyl, trimethylsilyl, or triethylsilyl. In an aspect of the process of the invention, P is t-butyloxycarbonyl.
In Step A of the process of the invention, the pyrazine carboxamide of Formula II* in a mixture with a solvent is hydrogenated, optionally in the presence of a hydrogenation catalyst, to form the corresponding piperazine carboxamide.
Suitable solvents include organic compounds, or mixtures thereof, which are chemically inert under the reaction conditions employed in Step A and which can also dissolve, suspend, and/or disperse Compound II* during the hydrogenation. Suitable solvents can be selected from the group consisting of C3-C12 linear and branched alkanes, C1-C6 linear and branched halogenated alkanes, C5-C7 cycloalkanes, C6-C10 aromatic hydrocarbons, dialkyl ethers wherein each alkyl is independently a C1-C6 alkyl, C4-C8 dialkoxyalkanes, C4-C6 cyclic ethers and diethers, C6-C8 aromatic ethers, and C1-C6 alkyl alcohols. Exemplary solvents include carbon tetrachloride, chloroform, methylene chloride, 1,2-dichloroethane (DCE), 1,1,2-trichloroethane (TCE), 1,1,2,2-tetrachloroethane, cyclohexane, toluene, o- and m- and p-xylene, ethylbenzene, ethyl ether, MTBE, THF, dioxane, 1,2-dimethoxyethane (DME), anisole, phenetole, methanol, ethanol, n- and iso-propanol, and tert-butyl alcohol.
In one embodiment, the solvent is selected from the group consisting of C2-C6 linear and branched halogenated alkanes, dialkyl ethers wherein each alkyl is independently a C1-C4 alkyl, C4-C6 cyclic ethers and diethers, and C1-C4 alkyl alcohols. In an aspect of the preceding embodiment, the solvent is a C1-C4 alkyl alcohol. In another aspect of the preceding embodiment, the solvent is methanol or ethanol.
The solvent can also be a mixture comprising water and one or more organic co-solvents. Suitable co-solvents include the organic solvents set forth in the preceding two paragraphs. In one embodiment, the co-solvent is a C1-C6 monohydric alcohol. In an aspect of this embodiment, the co-solvent is methanol or ethanol. The water can comprise from about 5 to about 95 volume percent based on the total volume of solvent.
The hydrogenation of pyrazine carboxamide II* can be conducted over a wide range of temperatures, although the temperature is typically in the range of from about xe2x88x9225 to about 200xc2x0 C. (e.g., from about xe2x88x9220 to about 100xc2x0 C.). In one embodiment, the temperature is in the range of from about 0 to about 80xc2x0 C. In another embodiment, the temperature is from about 15 to about 60xc2x0 C.
The pressure is not a critical aspect of the process of the invention, although atmospheric and superatmospheric pressures tend to be expedient. In one embodiment, the pressure is at least about 15 psia (103 kPa). In another embodiment, the pressure is in the range of from about 10 psia (68.9 kPa) to about 10,000 psia (68,950 kPa) (e.g., from about 50 psia (345 kPa) to about 1,000 psia (6,895 kPa)).
In one embodiment, the hydrogenation is conducted at a temperature in the range of from about 10 to about 100xc2x0 C. and at a pressure of from about 2 psig (115 kPa) to about 1000 psig (6996 kPa). In another embodiment, the hydrogenation is conducted at a temperature in the range of from about 15 to about 60xc2x0 C. and at a pressure in the range of from about 5 psig (135.8 kPa) to about 40 psig (377.1 kPa).
Any catalyst which is capable of expediting the hydrogenation of the pyrazine ring in Compound II* may be employed in the process of the invention. Typically, the catalyst comprises one or more transition metals, or compounds thereof, and especially comprises one or more of the Group VIII metals (or compounds thereof) as set forth in the Periodic Table of the Elements (see, e.g., the 78th edition of the Handbook of Chemistry and Physics, CRC Press (1997)). The metals can be employed in elemental form or as compounds (e.g., as oxides, hydroxides, or halides). Suitable hydrogenation catalysts include palladium, rhenium, rhodium, platinum, or nickel. The catalyst can be supported or unsupported. Suitable catalyst supports include carbon, silica, alumina, silicon carbide, aluminum fluoride, and calcium fluoride. Palladium is particularly suitable for use in the process of the invention. Exemplary palladium catalysts include Pd.black (i.e., fine metallic palladium particles), Pd/C (i.e., palladium on a carbon support), and Pd(OH)2/C.
The hydrogen source is typically hydrogen gas, optionally in admixture with a carrier gas that is inert to the process of the invention (e.g., nitrogen or a noble gas such as helium or argon).
The hydrogenation can be carried out in batches or continuously in various types of reactors such as a fixed bed reactor or an agitated slurry reactor in which the slurry of gas, solvent, pyrazine carboxamide II*, and catalyst is continuously agitated by mechanical or gas means. A suitable reaction vessel for relatively small scale, batch-wise hydrogenations is an autoclave equipped with a stirrer or rocker to agitate the reaction mixture. In a batch process, the order of addition of pyrazine carboxamide II, solvent, and hydrogenation catalyst to the reaction vessel (also referred to herein as the reaction xe2x80x9cpotxe2x80x9d) is not critical. The reaction components can, for example, be added concurrently, either together or separately, or they can be added sequentially in any order. In one embodiment, Compound II pre-mixed with the solvent is charged to the reaction vessel followed by addition of the catalyst. The hydrogenation can then be conducted by charging hydrogen gas, optionally in admixture with one or more inert gases, to the vessel containing the mixture comprising pyrazine carboxamide II*, solvent, and catalyst, and then agitating the mixture under reaction conditions.
Any amount of catalyst and hydrogen can be employed which results in the formation of at least some of Compound III*. Of course, the maximum conversion of Compound III* and maximum yield of Compound III* is normally desired, and relative proportions of reactants and reagents suitable for this purpose are typically employed.
The uptake of hydrogen is not a critical process parameter, although at least a stoichiometric amount of hydrogen gas is typically employed.
The amount of catalyst employed in Step A is suitably at least about 0.01 mole percent transition metal (e.g., Pd), and is typically in the range of from about 0.01 to about 5 (e.g., from about 0.1 to about 5) mole percent transition metal, based on the total moles of transition metal and Compound II*. In one embodiment, the amount of catalyst is in the range of from about 1 to about 5 (e.g., from about 2 to about 3) mole percent transition metal. In another embodiment, the catalyst comprises palladium (e.g., Pd/C or Pd(OH)2/C), and the amount of palladium catalyst is in the range of from about 1 to about 5 mole percent.
The yield of piperazine carboxamide III* in Step A can be at least about 80% (e.g., from about 85% to about 99%), and are often at least about 85% (e.g., from about 90% to about 99%)
Step B of the process of the invention involves the resolution of the S-carboxamide isomer from the racemic piperazine carboxamide III* resulting from hydrogenation step A, via the formation and separation of diastereomeric salts. Suitable chiral acids for use in Step (b1) include optically active forms of tartaric acid, mandelic acid, camphoric acid, 10-camphorsulfonic acid, pyroglutamic acid, O,O-diacetyltartaric acid, O,O-dibenzoyltartaric acid, O,O-di-4-toluyltartaric acid, and N-acetyl derivatives of amino acids such as N-acetylleucine. A preferred chiral acid is (S)-camphorsulfonic acid or (R)-camphorsulfonic acid. The chiral acid is especially (S)-camphorsulfonic acid, and the crystallized (S)-camphorsulfonate salt resulting from crystallizing step (b2) is a mono- or bis-salt of the S-isomer. The amount of chiral acid employed in Step B is typically in the range of from about 0.5 to about 3 equivalents per equivalent of racemic piperazine carboxamide III.
The solvent can be any chemically inert organic or inorganic substance, or combinations thereof, which can dissolve Compound III* and the chiral acid. Suitable solvents include water, C1-C6 monohydric alcohols (e.g., methanol, ethanol, n-propanol, n-butanol, n-pentanol, isopropanol, and sec-butyl alcohol), C2-C8 polyhydric alcohols (e.g., ethylene glycol, propylene glycol, and glycerol), C2-C4 nitriles (e.g., acetonitrile and propionitrile), N,N-di-C1-C6 alkyl tertiary amides of C1-C6 alkylcarboxylic acids (e.g., DMF), aliphatic C2-C6 ethers and di-ethers (e.g., ethyl ether, MTBE and dimethoxyethane), C4-C6 cyclic ethers and di-ethers (e.g., THF and dioxane), and combinations of two or more of the foregoing. In one embodiment, the solvent is selected from the group consisting of C1-C6 monohydric alcohols, aliphatic C2-C6 ethers and di-ethers and C4-C6 cyclic ethers and di-ethers. In an aspect of the preceding embodiment, the solvent is an alcohol such as methanol or ethanol. In another embodiment, the solvent is the combination of a C1-C6 monohydric alcohol and a C1-C4 nitrile. In an aspect of the preceding embodiment, the solvent is a mixture of ethanol and acetonitrile.
In another embodiment, the solvent is a mixture comprising water and at least one organic co-solvent. In an aspect of this embodiment, water comprises at least about 2 volume percent of the solvent (e.g., from about 2 to about 95 volume percent) based on the total volume of solvent. In another aspect of this embodiment, the aqueous solvent comprises from about 2 to about 70 volume percent (e.g., from about 5 to about 50 volume percent) water, with the balance of the solvent being organic co-solvent. Suitable co-solvents include the organic solvents set forth in the preceding paragraph. In one embodiment, the co-solvent is a C1-C6 monohydric alcohol optionally in combination with a C1-C4 nitrile. In an aspect of this embodiment, the solvent is water, ethanol, and acetonitrile.
The crystallization of the S- or R-isomer as set forth in Step (b2) above can be accomplished using conventional techniques, such as by cooling the solution or by concentrating the solution via vacuum or evaporative removal of solvent, and optionally seeding the solution with the appropriate crystal salt. If the resulting crystals are predominantly the desired S-isomer, the crystals can then be separated by filtration and followed optionally by the washing and drying of the filter cake. If the precipiated crystals are predominantly the R-isomer, a salt which contains predominantly the S-isomer can be obtained from the mother liquor, such as by evaporative or vacuum removal of the solvent.
The yield of the S-carboxamide isomer in Step B can be in a range of from about 20% to about 40%, and is often from about 30% to about 40%, based upon the racemic piperazine carboxamide. (The yield based upon the desired S-enantiomer is twice these values; i.e., from about 40% to about 80%, and often from about 60% to about 80%.)
Step C of the process of the invention involves breaking the crystallized salt by treating the S-isomer-containing salt with base and sequentially or concurrently treating the S-isomer with a nitrogen-protecting agent to obtain piperazine carboxamide I*. Suitable bases for breaking the recovered S-isomer include bases selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, alkali metal oxides, C1-C6 alkoxides of alkali metals, alkaline earth metal hydroxides, alkaline earth metal oxides, tetra (C1-C4 alkyl)ammonium hydroxides, and tri-(C1-C4 alkyl)amines. Exemplary bases include hydroxides, carbonates, and oxides of lithium, sodium and potassium; methoxides, ethoxides, and n- and iso-propoxides of lithium, sodium, and potassium; tetramethyl- and tetraethyl-ammonium hydroxide; triethylamine; and diisopropylethylamine. In one embodiment, the base is selected from the group consisting of alkali metal hydroxides. In an aspect of the preceding embodiment, the base is NaOH or KOH.
The base can also be an alkanolamine (e.g., ethanolamine), a hydroxylamine (e.g., hydroxylamine per se, N-methylhydroxylamine, N,N-dimethylhydroxylamine, or N-ethylhydroxylamine), or a diamine (e.g., ethylenediamine, tetramethylenediamine, or hexamethylenediamine).
A typical procedure can employ an aqueous base (e.g., aqueous NaOH), wherein the crystallized salt is slurried in an organic solvent and the slurry is mixed with aqueous base resulting in a solution or a biphasic mixture, followed by addition of and reaction with the nitrogen-protecting agent (e.g., Boc2O). The formation of the slurry and the biphasic mixture/solution is suitably conducted at temperatures in the range of from about 0 to about 100xc2x0 C., and is typically conducted at a temperature of from about 10 to about 60xc2x0 C. In one embodiment, the temperature is in the range of from about 15 to about 35xc2x0 C. The organic solvent can suitably be selected from C1-C12 linear and branched alkanes, C1-C12 linear and branched halogenated alkanes, C5-C10 cycloalkanes, C6-C14 aromatic hydrocarbons, dialkyl ethers wherein each alkyl is independently a C1-C10 alkyl, C4-C8 dialkoxyalkanes, C4-C8 cyclic ethers and diethers, C6-C8 aromatic ethers, C2-C10 dialkyl ketones wherein each alkyl is independently C1-C8 alkyl, C1-C6 alkyl esters of C1-C6 alkylcarboxylic acids, primary C1-C10 alkyl alcohols, secondary C3-C10 alkyl alcohols, tertiary C4-C10 alkyl alcohols, primary amides of C1-C6 alkylcarboxylic acids, Nxe2x80x94C1-C6 alkyl secondary amides or N,N-di-C1-C6 alkyl tertiary amides of C1-C6 alkylcarboxylic acids, C2-C6 aliphatic nitriles, C7-C10 aromatic nitriles, and mixtures thereof. Exemplary solvents include carbon tetrachloride, chloroform, methylene chloride, 1,2-dichloroethane (DCE), 1,1,2-trichloroethane (TCE), 1,1,2,2-tetrachloroethane, cyclohexane, toluene, o- and m- and p-xylene, ethylbenzene, ethyl ether, MTBE, THF, dioxane, 1,2-dimethoxyethane (DME), anisole, phenetole, acetone, methyl ethyl ketone (MEK), methyl acetate, ethyl acetate, IPAc, ethanol, n- and iso-propanol, tert-butyl alcohol, dimethylformamide (DMF), acetonitrile, propionitrile, benzonitrile, and p-tolunitrile.
Another typical procedure can employ a non-aqueous base, wherein the crystallized salt is suspended in organic solvent, optionally including a small amount of water (e.g., from about 0 to about 10 volume percent) as co-solvent, the suspension mixed with an organic base, and the mixture stirred until homogeneous, followed by addition of and reaction with the nitrogen-protecting agent. The formation of the suspension and the homogeneous mixture is suitably conducted at temperatures in the range of from about 0 to about 100xc2x0 C., and is typically conducted at a temperature of from about 10 to about 60xc2x0 C. (e.g., from about 15 to about 35xc2x0 C.). Suitable organic solvents include those set forth in the preceding paragraph. In one embodiment, the solvent is a mixture of C2-C4 aliphatic nitrile and a C1-C4 alkyl ester of a C1-C4 alkylcarboxylic acid (e.g., a mixture of acetonitrile and isopropyl acetate).
It is normally desired to completely break the crystallized salt so as to obtain the free base (S)-piperazine carboxamide. Accordingly, the base is typically employed in an amount of at least about 2 equivalents per equivalent of crystallized salt.
Treating with base to break the salt in Step C also includes eluting a solution of the crystalline salt through a suitable ion exchange column, such that the chiral acid and the piperazine amide elute separately. The crystalline salt solution can be prepared by dissolving the salt crystals obtained in Step B in a suitable solvent (e.g., the solvents set forth above in the description of Step B). In the case where the desired salt crystals are present in the Step B mother liquor (i.e., Step (b4)), the mother liquor can be passed directly through the column and thereby avoiding isolation of the salt crystal. The eluted piperazine carboxamide can then be reacted with a suitable nitrogen protecting agent to afford Compound I*.
While any amount of nitrogen-protecting agent can be employed which results in the formation of at least some of Compound I*, the amount of agent typically employed is that which can maximize the conversion of the S-isomer of III* to I*. Accordingly, the amount of nitrogen-protecting agent is suitably at least about 1 equivalent per equivalent of III*. In one embodiment, the amount of nitrogen-protecting agent is in the range of from about 1 to about 1.5 equivalents per equivalent of III*.
Yields of at least about 85% (e.g., from about 90% to about 99%) for Compound I* can be obtained in Step C.
Another aspect of the invention is a process for racemizing an optically pure or enriched piperazine carboxamide selected from: 
which comprises treating the piperazine carboxamide with a strong base in a solvent at a temperature in the range of from about 0 to about 250xc2x0 C.; wherein Pxe2x80x2 is either hydrogen or a nitrogen-protecting group P as defined above; and R6A, Rs, Rt and Ru are each as defined above. Suitable strong bases include of alkali metal hydroxides and C1-C6 alkoxides of alkali metals. Exemplary strong bases include the methoxides, ethoxides, n- and iso-propoxides, and tert-butoxides of lithium, sodium, and potassium. Suitable solvents include the organic solvents set forth above as useful in Step C. The reaction temperature is more typically in the range of from about 40 to about 120xc2x0 C.
In an embodiment of the racemization process, the starting piperazine carboxamide is the R-isomer: 
The mother liquor from Step (b3) or the salt crystals from Step (b4) can be a source of the R-isomer, wherein the diastereomeric salt containing the isomer can be broken by treating with base in the same manner as that described above in Step C for the S-isomer, to afford the R-isomer. Once racemized the piperazine carboxamide can be subjected to the resolution process as described in Step B above to obtain additional quantities of the desired S-isomer.
An embodiment of the invention is a process which comprises Steps A, B and C as set forth above, and which further comprises:
(Z) reacting a pyrazine carboxylic acid of Formula (IV*): 
xe2x80x83with R6ANH2, or an acid salt thereof, in the presence of a coupling agent to obtain pyrazine carboxamide II*;
wherein R6A, Rs, Rt and Ru are each as defined above.
Acid salts of the amine, R6ANH2, suitable for use in Step Z include salts of inorganic acids (e.g., HCl, sulfuric acid, nitric acid, etc.) and of organic acids (e.g., acetic acid, trifluoroacetic acid, alkyl and aryl sulfonic acids, etc.)
While any amount of the Compound IV* can be employed which results in the formation of at least some of Compound II*, the maximum conversion of Compound IV* and maximum yield of Compound II* is normally desired. Accordingly, the-amount of Compound IV* typically employed in Step Z is at least about one equivalent per equivalent of the amine. In one embodiment, the amount of Compound IV* is in the range of from about 0.5 to about 5 equivalents per equivalent of amine. In another embodiment, the amount of Compound IV* is in the range of from about 0.9 to about 2 (e.g., from about 1 to about 1.5) equivalents per equivalent of amine.
The coupling agent in Step Z can be any organic compound which facilitates the amidation of the carboxylic acid group in IV* by R6ANH2. Suitable coupling agents include carbodiimides (e.g., such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, EDC, and the like), N,Nxe2x80x2-carbonyldiimidazole, POCl3, TiCl4, SO2ClF, and chlorosulfonyl isocyanate. In one embodiment, the coupling agent is EDC. In an aspect of the preceding embodiment, the coupling agent is EDC in combination with HOBT.
While any amount of coupling agent can be employed which results in the formation of at least some of Compound II*, the maximum conversion of Compound IV* and maximum yield of Compound II* is normally desired. Accordingly, the amount of coupling agent typically employed in Step Z is at least about one equivalent per equivalent of IV*. In one embodiment, the amount of coupling agent is in the range of from about 1 to about 5 equivalents per equivalent of IV*. In another embodiment, the amount of coupling agent is in the range of from about 1 to about 2 equivalents per equivalent of IV*.
The amidation of Compound IV* can be conducted over a wide range of temperatures, although the temperature is typically in the range of from about xe2x88x9220 to about 150xc2x0 C. (e.g., from about xe2x88x9215 to about 120xc2x0 C.). In one embodiment, the temperature is in the range of from about xe2x88x925 to about 65xc2x0 C. In another embodiment, the temperature is from about 0 to about 50xc2x0 C. In still another embodiment, the temperature is from about 10 to about 35xc2x0 C.
In a typical procedure, the pyrazine carboxylic acid IV* is dissolved, dispersed or suspended in an organic solvent, followed by the sequential addition of the amine and the coupling agent. The mixture is maintained at reaction temperature for a period sufficient to achieve maximum conversion, after which the amidated product is recovered from the reaction mixture by conventional separation and isolation procedures.
Organic solvents suitable for use in Step Z include the C1-C12 linear and branched alkanes, C1-C12 linear and branched halogenated alkanes, C5-C10 cycloalkanes, C6-C14 aromatic hydrocarbons, dialkyl ethers wherein each alkyl is independently a C1-C10 alkyl, C4-C8 dialkoxyalkanes, C4-C8 cyclic ethers and diethers, C6-C8 aromatic ethers, C2-C10 dialkyl ketones wherein each alkyl is independently C1-C8 alkyl, C1-C6 alkyl esters of C1-C6 alkylcarboxylic acids, primary C1-C10 alkyl alcohols, secondary C3-C10 alkyl alcohols, tertiary C4-C10 alkyl alcohols, primary-amides of C1-C6 alkylcarboxylic acids, Nxe2x80x94C1-C6 alkyl secondary amides or N,N-di-C1-C6 alkyl tertiary amides of C1-C6 alkylcarboxylic acids, C2-C6 aliphatic nitriles, C7-C10 aromatic nitriles, and mixtures thereof.
If desired, the progress of the reaction in any one or all of Steps Z, A, B and C can be followed by monitoring the disappearance of a reactant (e.g., Compound II* or H2 in Step A) and/or the appearance of the product (e.g., III* in step A) using such analytical techniques as TLC, HPLC, NMR or GC.
Yields of at least about 70% (e.g., from about 70% to about 90%) for pyrazine carboxamide II* can be obtained in Step Z, and yields of from about 85% to about 95% can often be achieved.
Another embodiment of the process of the invention is a process for preparing a nitrogen-protected piperazine carboxamide of formula A1: 
wherein P is a nitrogen-protecting group and the process comprises:
(A) hydrogenating a pyrazine carboxamide of formula A2: 
xe2x80x83in a solvent and in the presence of a transition metal catalyst to obtain a piperazine carboxamide of formula A3: 
(B) resolving the S-carboxamide isomer of Compound A3 by:
(b1) forming a solution comprising Compound A3, (S)-camphorsulfonic acid, and solvent; and
(b2) crystallizing from the solution a salt which contains predominantly the S-isomer; and
(C) breaking the separated crystal salt of the S-carboxamide isomer by treating the salt with base, and treating the resulting free base S-isomer with a nitrogen-protecting agent to obtain piperazine carboxamide A1.
The general reaction conditions and procedures, choice of solvents, choice and/or amounts of reactants and reagents described earlier for Steps A, B and C apply to Steps A, B and C of this embodiment as well. The crystallization in Step (b2) can optionally be assisted by seeding the solution with the (S)-camphorsulfonate salt of the (S)-isomer.
In an aspect of this embodiment, the resolution of the S-carboxamide isomer is conducted in a solvent consisting of acetonitrile, ethanol, and water with from about 1.2 to about 2.0 equivalents (e.g., from about 1.5 to about 1.9 equivalents) of (S)-CSA per equivalent of racemic A3. In a preferred aspect of this embodiment, the resolution of the S-carboxamide isomer is conducted in a solvent consisting of acetonitrile, ethanol, and water with from about 1.2 to about 2.0 equivalents (e.g., from about 1.6 to about 1.8 equivalents; or about 1.7 equivalents) of (S)-CSA per equivalent of racemic A3, wherein water constitutes from about 2 to about 7 weight percent (e.g., from about 4 to about 5 weight percent) of the solvent and the volume ratio of acetonitrile to ethanol is in the range of from about 9:1 to about 6:4.
The enantiomeric excess of the resulting salt can be upgraded by (i) forming a slurry of the salt in a solvent system comprising acetonitrile, ethanol and water (e.g., from about 50 to about 95 volume percent acetonitrile, from about 49 to about 4 volume percent ethanol, and from about 1 to about 5 volume percent water; another example: from about 1:1 to about 15:1 (v/v) acetonitrile:95% ethanol), (ii) aging the slurry by heating it for a period of time (e.g., at a temperature of from about 50 to about 90xc2x0 C. for at least about one hour), and then (iii) cooling the slurry (e.g., to a temperature in the range of from about 0 to about 30xc2x0 C.). The resulting crystals have an increased ee and can be recovered by conventional means (e.g., filtration, washing with the slurry solvent, and drying).
Another embodiment of the process is a process which comprises Steps A, B and C as set forth in the preceding embodiment, and which further comprises:
(Z) reacting a pyrazine carboxylic acid of Formula A4: 
xe2x80x83with CF3CH2NH2, or an acid salt thereof, in the presence of EDC and HOBT to obtain pyrazine carboxamide A2.
The general reaction conditions and procedures, choice of solvents, choice and/or amounts of reactants and reagents described earlier for Step Z apply to Step Z of this embodiment as well.
Another embodiment of the present invention is a compound of Formula (V*): 
wherein P is a nitrogen-protecting group. In an aspect of this embodiment, P is Boc.